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University of California Berkeley
Regional Oral History Office University of California
The Bancroft Library Berkeley, California
Program in the History of the Biological Sciences and Biotechnology
Richard Scheller, PhD.
CONDUCTING RESEARCH IN ACADEMIA, DIRECTING RESEARCH AT GENENTECH
With an Introduction by
Susan K. McConnell
Interviews Conducted by
Sally Smith Hughes, Ph.D.
in 200 land 2002
Copyright 2002 by The Regents of the University of California
Since 1954 the Regional Oral History Office has been interviewing leading participants in or well-placed
witnesses to major events in the development of northern California, the West, and the nation. Oral
history is a method of collecting historical information through tape -recorded interviews between a
narrator with firsthand knowledge of historically significant events and a well-informed interviewer, with
the goal of preserving substantive additions to the historical record. The tape recording is transcribed,
lightly edited for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is
indexed, bound with photographs and illustrative materials, and placed in The Bancroft Library at the
University of California, Berkeley, and in other research collections for scholarly use. Because it is
primary material, oral history is not intended to present the final, verified, or complete narrative of
events. It is a spoken account, offered by the interviewee in response to questioning, and as such it is
reflective, partisan, deeply involved, and irreplaceable.
************************************
All uses of this manuscript are covered by a legal agreement between The
Regents of the University of California and Richard Scheller dated August 17, 2001.
The manuscript is thereby made available for research purposes. All literary rights in the
manuscript, including the right to publish, are reserved to The Bancroft Library of the
University of California, Berkeley. No part of the manuscript may be quoted for
publication without the written permission of the Director of The Bancroft Library of the
University of California, Berkeley.
Requests for permission to quote for publication should be addressed to the
Regional Oral History Office, 486 Bancroft Library, Mail Code 6000, University of
California, Berkeley 94720-6000, and should include identification of the specific
passages to be quoted, anticipated use of the passages, and identification of the user.
It is recommended that this oral history be cited as follows:
Richard Scheller, "Conducting Research in Academia, Directing Research at
Genentech," an oral history conducted in 200 land 2002 by Sally Hughes for
the Regional Oral History Office, The Bancroft Library, University of
California, Berkeley, 2002.
Copy no.
Richard Scheller, 2002
TABLE OF CONTENTS-Richard Scheller, Ph.D.
BIOTECHNOLOGY SERIES HISTORY i
BIOTECHNOLOGY SERIES LIST iii
INTRODUCTION by Susan K. McConnell v
INTERVIEW HISTORY by Sally Smith Hughes vii
BIOGRAPHICAL INFORMATION ix
I FAMILY BACKGROUND AND EDUCATION
Childhood Wish to Become a Scientist 1
Undergraduate, University of Wisconsin, Madison, 1971-1975 2
Biochemistry Major 2
Undergraduate Research 3
Graduate Student, California Institute of Technology, 1975-1980 4
Richard Dickerson, Arthur Riggs, and Research on lac Represser Protein 4
DNA Synthesis 5
Dickerson s Laboratory 6
Collaborating with Herbert Boyer to Clone lac Operator DNA
Scheller s DNA Linkers 9
No Memory of the Introduction of Recombinant DNA Technology 10
Dickerson, Riggs, and Keiichi Itakura 10
Applying Recombinant DNA to Gene Expression in Animals 1 1
The Recombinant DNA Controversy 13
Richard Sinsheimer s Concern about Recombinant DNA 15
Interacting with Leroy Hood s Laboratory 16
The Sea Urchin as Experimental Organism 17
Scheller s Research on Embryonic Development 17
Scheller s Research on the Actin Genes 18
Postdoctoral Fellow in Neuroscience, Columbia, 1981-1982 18
Reductionism 18
Eric Kandel 19
Scheller Clones the Gene for Egg-laying Hormone 19
Choosing Columbia for a Postdoc 21
Interacting with Eric Kandel 22
H FACULTY MEMBER, STANFORD, 1982-2000 24
Assistant Professor, Department of Biological Sciences 24
Deciding on Stanford 24
Corey Goodman as Colleague in Neurobiology 25
Continuing Research on Molecular Development in Aplysia 26
Department of Molecular & Cellular Physiology (1990-1993) and Howard Hughes
Investigator (1990-1994), Stanford University Medical Center 27
The New Appointments 27
Scheller s Wide-ranging Interests 28
Corporate Consultations and Comparisons of Academic and Industry Science 29
Limitations on Outside Activities Imposed by the Hughes Institute 29
DIRECTOR OF SCIENTIFIC RESEARCH, GENENTECH, JANUARY 200 1 -PRESENT 3 1
Decision to Join Genentech 3 1
Need for a Change 3 1
Criticism of the System of Scientific Publication 3 1
Seeing Opportunities at Genentech 32
Establishing Goals with Arthur Levinson 33
Research to Produce Products 34
Dealing with Genentech s Culture 35
Fostering Scientific Interaction 36
Scientists at Genentech and Stanford 37
Scheller s Recruitment 37
Dennis Henner and David Martin, Previous Directors of Research 38
Genentech s Openness About Science 39
Intellectual Property in Biotechnology 40
Gene Patenting 40
Emphasis on Patenting at Stanford and Genentech 42
Scheller s Programmatic Changes 42
Scheller s Postdoctoral Fellows Follow Him to Genentech 43
Prevailing Stigma against Industry Scientists 44
Genen tech s Drug Production Capability 45
Genentech s Research Review Committee 46
The Hoffmann-La Roche Presence at Genentech 46
Scheller s Scientific "Instinct" 47
Scheller s Contributions 47
Thoughts on the Oral History Process 47
Further Discussion of Scheller s Graduate Student Years at Caltech 48
More on the First Cloning of Synthetic DNA 48
Somatostatin: Genentech s First Research Project 50
Deciding on DNA Synthesis 50
Choosing Somatostatin as the Molecule to Clone 50
A Failed Attempt at Caltech 5 1
Scheller s Confidence in Bacterial Production of Human Peptides 52
Initial Failure 53
Somatostatin Research to Bolster a Patent 54
Stock Options for a Graduate Student 54
Scheller s Confidence in Genentech s Success 55
Biology Begins to Become Corporate 55
Biologists with Corporate Ties 55
Jealousy as a Motive for Criticizing Commercialization 56
Observations on Genentech Culture 57
Encouraging Passion for Science 58
TAPE GUIDE 61
APPENDIX 63
INDEX 85
1
BIOTECHNOLOGY SERIES HISTORY-Sally Smith Hughes, Ph.D.
Genesis of the Program in the History of the Biological Sciences and Biotechnology
In 1996 The Bancroft Library launched the Program in the History of the Biological Sciences and
Biotechnology. Bancroft has strong holdings in the history of the physical sciences the papers of E.O.
Lawrence, Luis Alvarez, Edwin McMillan, and other campus figures in physics and chemistry, as well as
a number of related oral histories. Yet, although the university is located next to the greatest
concentration of biotechnology companies in the world, Bancroft had no coordinated program to
document the industry or its origins in academic biology.
When Charles Faulhaber arrived in 1995 as Bancroft s director, he agreed on the need to
establish a Bancroft program to capture and preserve the collective memory and papers of university and
corporate scientists and the pioneers who created the biotechnology industry. Documenting and
preserving the history of a science and industry which influences virtually every field of the life sciences
and generates constant public interest and controversy is vital for a proper understanding of science and
business in the late twentieth and early twenty-first centuries.
The Bancroft Library is the ideal location to carry out this historical endeavor. It offers the
combination of experienced oral history and archival personnel and technical resources to execute a
coordinated oral history and archival program. It has an established oral history series in the biological
sciences, an archival division called the History of Science and Technology Program, and the expertise to
develop comprehensive records management plans to safeguard the archives of individuals and
businesses making significant contributions to molecular biology and biotechnology. It also has
longstanding cooperative arrangements with UC San Francisco and Stanford University, the other
research universities in the San Francisco Bay Area.
In April 1996, Daniel E. Koshland, Jr. provided seed money for a center at The Bancroft Library
for historical research on the biological sciences and biotechnology. And then, in early 2001, the
Program in the History of the Biological Sciences and Biotechnology was given great impetus by
Genentech s generous pledge to support documentation of the biotechnology industry.
Thanks to these generous gifts, Bancroft has been building an integrated collection of research
materials-oral history transcripts, personal papers, and archival collections-related to the history of the
biological sciences and biotechnology in university and industry settings. A board composed of
distinguished figures in academia and industry advises on the direction of the oral history and archival
components. The Program s initial concentration is on the San Francisco Bay Area and northern
California. But its ultimate aim is to document the growth of molecular biology as an independent field
of the life sciences, and the subsequent revolution which established biotechnology as a key contribution
of American science and industry.
Oral History Process
The oral history methodology used in this program is that of the Regional Oral History Office,
founded in 1954 and producer of over 2,000 oral histories. The method consists of research in primary
and secondary sources; systematic recorded interviews; transcription, light editing by the interviewer,
and review and approval by the interviewee; library deposition of bound volumes of transcripts with table
of contents, introduction, interview history, and index; cataloging in UC Berkeley and national online
library networks; and publicity through ROHO news releases and announcements in scientific, medical,
and historical journals and newsletters and via the ROHO and UCSF Library Web pages.
Oral history as a historical technique has been faulted for its reliance on the vagaries of memory,
its distance from the events discussed, and its subjectivity. All three criticisms are valid; hence the
necessity for using oral history documents in conjunction with other sources in order to reach a
reasonable historical interpretation. Yet these acknowledged weaknesses of oral history, particularly its
subjectivity, are also its strength. Often individual perspectives provide information unobtainable
through more traditional sources. Oral history in skillful hands provides the context in which events
occur the social, political, economic, and institutional forces which shape the course of events. It also
places a personal face on history which not only enlivens past events but also helps to explain how
individuals affect historical developments.
Emerging Themes
Although the oral history program is still in its initial phase, several themes are emerging. One is
"technology transfer," the complicated process by which scientific discovery moves from the university
laboratory to industry where it contributes to the manufacture of commercial products. The oral histories
show that this trajectory is seldom a linear process, but rather is influenced by institutional and personal
relationships, financial and political climate, and so on.
Another theme is the importance of personality in the conduct of science and business. These
oral histories testify to the fact that who you are, what you have and have not achieved, whom you know,
and how you relate have repercussions for the success or failure of an enterprise, whether scientific or
commercial. Oral history is probably better than any other methodology for documenting these personal
dimensions of history. Its vivid descriptions of personalities and events not only make history vital and
engaging, but also contribute to an understanding of why circumstances occurred in the manner they did.
Molecular biology and biotechnology are fields with high scientific and commercial stakes. As
one might expect, the oral histories reveal the complex interweaving of scientific, business, social, and
personal factors shaping these fields. The expectation is that the oral histories will serve as fertile ground
for research by present and future scholars interested in any number of different aspects of this rich and
fascinating history.
Location of the Oral Histories
Copies of the oral histories are available at the Bancroft, UCSF, and UCLA libraries. They also
may be purchased at cost through the Regional Oral History Office. Some of the oral histories, with
more to come, are available on The Bancroft Library s History of the Biological Sciences and
Biotechnology Website: http://bancroft.berkeley.edu/Biotech/.
Sally Smith Hughes, Ph.D.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
October 2002
ir The three criticisms leveled at oral history also apply in many cases to other types of
documentary sources.
Ill
December 2002
ORAL HISTORIES ON BIOTECHNOLOGY
Program in the History of the Biological Sciences and Biotechnology
Paul Berg, Ph.D., "A Stanford Professor s Career in Biochemistry, Science Politics, and the Biotechnology
Industry," 2000
Mary Betlach, Ph.D., "Early Cloning and Recombinant DNA Technology at Herbert W. Boyer s UCSF
Laboratory," 2002
Herbert W. Boyer, Ph.D., "Recombinant DNA Science at UCSF and Its Commercialization at Genentech," 2001
Thomas J. Kiley, "Genentech Legal Counsel and Vice President, 1976-1988, and Entrepreneur," 2002
Dennis G. Kleid, Ph.D., "Scientist and Patent Agent at Genentech," 2002
Arthur Komberg, M.D., "Biochemistry at Stanford, Biotechnology at DNAX," 1998
Fred A. Middleton, "First Chief Financial Officer at Genentech, 1978-1984," 2002
Thomas J. Perkins, "Kleiner Perkins, Venture Capital, and the Chairmanship of Genentech, 1976-1995," 2002
"Regional Characteristics of Biotechnology in the United States: Perspectives of Three Industry Insiders"
(Hugh D Andrade, David Holveck, and Edward Penhoet), 2001
Niels Reimers, "Stanford s Office of Technology Licensing and the Cohen/Boyer Cloning Patents," 1998
William J. Rutter, Ph.D., "The Department of Biochemistry and the Molecular Approach to Biomedicine at
the University of California, San Francisco: Volume I," 1998
Richard Scheller, Ph.D., "Conducting Research in Academia, Directing Research at Genentech," 2002
Robert A. Swanson, "Co-founder, CEO, and Chairman of Genentech, 1976-1996," 2001
Daniel G. Yansura, "Senior Scientist at Genentech," 2002
Oral histories in process:
Brook Byers
Stanley N. Cohen
Chiron Corporation
Roberto Crea
David V. Goeddel
Herbert Heyneker
Irving Johnson
Arthur Levinson
G. KirkRaab
William J. Rutter, Volume n
Axel Ullrich
Keith R. Yamamntn
IV
INTRODUCTION by Susan K. McConnell 1
"Whatever happened to the little boy with the chemistry set and the microscope?" Richard asked
me after spending a long day talking with lawyers and journalists a day in the life of the Director of
Research at Genentech, but for Richard, a day that also represented a diametrical shift from his past life
as professor at Stanford University.
Richard Scheller grew up in the suburbs of Milwaukee, Wisconsin, where he dreamed of
becoming a biochemist. To Richard s mother Marion, he was her "little scientist," and indeed she and his
father Dick bought him those chemistry sets and microscopes which occupied much of Richard s time
when he was little. To my knowledge he never blew anything up, but his early experiments did result in
many loud bangs at odd hours. The chemistry experiments (at least the ones using formal kits) were set
aside during Richard s teenage years, which were spent in what was for the late 1960s a pretty typical set
of rebellious behaviors, including membership in a rock band (I can personally attest that Richard cannot
carry a tune, so one must hope that the volume of the music made up for what I assume were certain
melodic insufficiencies) and the care and feeding of a very large snake that consumed mice. Fortunately
for her sanity, Richard s mother was unaware that the process of warming up frozen animal parts
involved the pots and pans she used for cooking dinners. Richard s teenage years were characterized by
what one might call a benign neglect of scholarly pursuits, accompanied by the growth of quite
prodigious amounts of hair. Nevertheless, by the time college rolled around, Richard refocused on his
scientific aspirations, entered the University of Wisconsin, buckled down to his studies, and got serious
about modem science.
I relate these stories because I think that the spirits of unconventionality and exploration have
suffused Richard s work as a scientist from the earliest stages. Richard loves being on the cutting edge.
Better still, Richard loves being the cutting edge. The most well known story about Richard is that as a
graduate student at Caltech, he worked with Genentech founders Boyer, Riggs and Itakura, synthesizing
the DNA encoding somatostatin and linkers. At the time, Genentech was more an idea than a reality;
there was no building to house the company and no cash to pay some kid to synthesize DNA, so Richard
was offered stock in exchange for a summer s worth of work. I personally think that he would have done
the work for free-it was completely different from the way in which any other graduate student was
spending the summer but the outcome a couple of years later was a photo of a 26-year-old-graduate
student on the front page of the Los Angeles Times, hair past his shoulders, grinning because the stock he
earned was now worth more than a million bucks. This was long before the days ofdot.com millionaires,
and of course the success and longevity of Genentech as a company has far surpassed these upstart
companies, but it is amusing to think of Richard as a forerunner of the brash kids who turned ideas into
new enterprises in the 90s.
Richard s success as an academic scientist was framed on his instinct for a good problem and his
nerve for taking big risks. Richard s postdoctoral work with Richard Axel and Eric Kandel at Columbia
represented a first breakthrough. With these two advisors, Scheller worked at the forefront of molecular
neuroscience, identifying genes that were involved in controlling behavior in the sea slug Aplysia
californica. In this project, Richard served as a conduit and catalyst between two extraordinary
intellects, representing two fields (molecular biology and neuroscience) that were struggling to find a
Susan McConnell and Richard Scheller are married.
VI
common language. Richard claims to have taught Kandel about DNA and to have taught Axel that
Aplysia is not a fish. These studies uncovered the first gene known to control a complex behavior (egg
laying) and earned Richard a faculty position at Stanford University. A less adventuresome or ambitious
scientist would have been content to continue to plug away in this system, cloning neuropeptide genes
and exploring the cell biology of egg laying. However, at the time that I first met Richard, he was
already gearing up for the major effort that would earn him world-wide recognition. With characteristic
ambition, Richard wanted to understand the molecular underpinnings of learning and memory. He
realized, though, that if learning involves long-lasting changes in synaptic transmission, then a deep
appreciation of the mechanisms underlying these changes could be achieved only if one understood the
basic molecular biology of the synapse. He set out to use biochemical methods to purify, sequence, and
clone every protein component of the synaptic vesicle, and by God, he pretty much did just that! Those
studies and the ones that followed are now viewed as classics, not only in the field of neuroscience but
because they laid the groundwork for understanding how membranes are trafficked to specific
compartments in all cells.
I believe that Richard s decision to leave academia and join (or, actually, re-join) Genentech was
practically inevitable and reflects his appetite for big challenges and his interest in different cultures.
Richard is an adventuresome traveler who immerses himself in the place he is visiting. Hell try just
about any local food (much to the distress of his digestive system) and loves to talk with local people and
fellow travelers. On our trips together, I may quit the campfire or the bar in the late evening, but Richard
will stay and talk until the last person disappears. The next day I ll hear all about local politics, the
bartender s children, and whatever gossip or complaints or teasing transpired. In many ways I view
Richard s decision to head Research at Genentech as one of these adventures in immersion. And immerse
himself in Genentech he has from the start, Richard has talked about the company as "we" and expresses
great pride in the company s traditions, policies, and successes. He is particularly proud of Genentech s
ability to bring new products to market, and (in paraphrasing a biotech analyst) Richard likes to boast,
"We make money the old-fashioned way~we sell stuff."
So while it is true that the daily life of Marion Scheller s "little scientist" is now quite different
than when he was at Stanford, the theme of adventure and change is a constant. For Richard, Genentech
is a great adventure indeed, in learning about business and realms of science into which he had never
before delved, about managing people and making decisions that affect human health and the lives of
thousands of employees, and most importantly about translating discoveries in basic science into
products that will improve the human condition.
Susan K. McConnell, Ph.D.
Professor of Biological Sciences
Stanford University
Stanford, California
December 17,2002
Vll
INTERVIEW HISTORY-Richard Scheller
Richard Scheller was interviewed for this oral history series on biotechnology because of his
early and current associations with Genentech. At the time of the first interview, Dr. Scheller was six
months into his appointment as senior vice president of research at Genentech, to which with some
fanfare he took office in January 2001 . His thoughts at the outset of a new career should be of interest,
particularly his observations on the similarities and differences between the interconnected worlds of
academic and industrial research.
As the reader will leam, Scheller s first brush with the company was as a Caltech graduate
student. Because of his experience in DNA synthesis which he had used in a project on the lac operator,
he was asked to try his hand at synthesizing DNA for the Genentech-sponsored project on somatostatin.
Scheller s attempt did not succeed, and he quickly dropped out of the project. But the stock that he
received in partial payment and nonchalantly socked away was to escalate in value a few years later at
Genentech s spectacular initial public offering on Wall Street, turning him into a temporary millionaire.
A good portion of the oral history has ostensibly nothing to do with Genentech but rather with
Scheller s remarkable career in neurobiology, first at Columbia and then for almost two decades at
Stanford. His work on neural transmitters in the model organism Aplysia, the sea slug, is better told in
his own words. From 1994 until his departure for Genentech, Scheller was a Howard Hughes Medical
Institute Investigator, a position denoting his high standing in the competitive world of basic biomedical
science. 1
In a deeper sense, Scheller s achievements in basic science and the associations he made with his
colleagues have everything to do with Genentech and his appointment to one of its most significant
positions. This is the justification, if any is needed, for including discussion of Scheller s non-Genentech
career. It was Scheller s reputation as a basic scientist which Art Levinson cited in a press release as a
main rationale for his appointment. Since Genentech does not have a program on neurobiology, one can
deduce that it was not the specifics of Scheller s scientific research that made him attractive to
Genentech. In the oral history, Scheller himself verifies that it was his general reputation as a basic
scientist that Genentech wished to enroll and which also gave him the moral authority to make decisions
affecting scientists who had been at work in the biotechnology industry far longer than he had.
Oral History Process
Three interviews were conducted in the conference room adjoining Scheller s office in Bldg. 12,
Genentech s new research facility. At the first interview, he emerged somewhat bleary-eyed from a five-
hour meeting of Genentech s executive committee. He nonetheless settled into the interview, enthused
by memories of his early exposure to science. He seemed to be fully engaged in this and subsequent
interviews. With the exception of a few pages, he did not review the transcripts.
Readers wishing more information on Scheller s basic science contributions should refer to an
interview conducted in 1989 in the possession of the Hagley Museum and Library, Wilmington,
Delaware.
Vlll
The reader will note that the discussion veers from strict chronological order. These interviews,
as well as others conducted at this time, were affected by the litigation Genentech was currently engaged
in with City of Hope. As a result, Genentech asked that discussion of its earliest projects-somatostatin,
insulin, and growth hormone-be deferred until the conclusion of the case. As a result, Scheller s
description of his work on somatostatin, constituting his first contact with Genentech, occurs out of order
in the third section. Also according to agreement with Genentech regarding the oral histories it
supported, its legal department received transcripts of all interviews to review solely for current legal
issues. As in all other instances to date, no changes were requested.
The Regional Oral History Office was established in 1954 to augment through tape-recorded
memoirs the Library s materials on the history of California and the West. Copies of all interviews are
available for research use in The Bancroft Library and in the UCLA Department of Special Collections.
The office is under the direction of Richard Candida Smith, Director, and the administrative direction of
Charles B. Faulhaber, James D. Hart Director of The Bancroft Library, University of California,
Berkeley.
Sally Smith Hughes, Ph.D.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
November 2002
Regional Oral History Office University of California
Room 486 The Bancroft Library Berkeley, California 94720
BIOGRAPHICAL INFORMATION
(Please write clearly. Use black ink.)
Your full name Richard H. Scheller
Date of birth 10 / 30 / 53 Birthplace Milwaukee, Wisconsin
Father s full name Richard W. Scheller
Occupation Hospital Director Birthplace Milwankpp, Wi^rnnsi n
Mother s full name Marion Scheller
Occupation Artis t Birthplace Milwaukee, Wisconsin
Your spouse/partner Susan McConnell
Occupation Professor Birthplace Crow Point, Indiana
Your children
Where did you grow up? Milwaukee, Wisconsin
Present community_ Stanford, California
Education__ Ph.D. Cal Tech
Occupation(s) Professor, Stanford ; Senior Vice President - Research. Cenentech
Areas of expertise Molecular Biology, Biochemistry, Physiology
Other interests or activities
Organizations in which you are active_
SIGNATURE IZwC M J{LUtf(/X M DATE: III 6/61
INTERVIEW WITH RICHARD SCHELLER, PH.D.
I FAMILY BACKGROUND AND EDUCATION
[Interview 1: August 16, 2001]##
Childhood Wish to Become a Scientist
Hughes: Please tell me about your family and early education.
Scheller: Oh my goodness. I was born and raised in Milwaukee, Wisconsin, in the Midwest. It was a
wonderful place to grow up. My father was a social worker and a hospital administrator. My
mother was a housewife for many years of our childhood and then went back and received her
bachelor s and master s degrees in art.
I always wanted to be a scientist. As a child I had chemistry sets and microscopes, and I
had a laboratory in the basement of our house. I would spend hours there doing experiments.
My mother used to call me her little scientist.
Hughes: What triggered your interest?
Scheller: I have absolutely no idea. I was just fascinated with the physical world around me and wanted
to understand it in logical terms. I can t really recall any specific trigger. My father and
mother are not scientists, my grandparents are not scientists, but somehow I believe being a
scientist is something innate in my DNA because it goes so far back.
Hughes: Did that interest continue all the way through school?
Scheller: Sure. I would say I was not an outstanding high school student. I was good in chemistry but
not particularly focused even though I knew I wanted to be a scientist. I actually even knew in
high school that I wanted to be a biochemist.
##This symbol indicates that a tape or tape segment has begun or ended. A guide to the tapes
follows the transcript.
Undergraduate, University of Wisconsin, Madison, 1971-1975
Biochemistry Major
Scheller: I knew that the University of Wisconsin in Madison was a very strong school for biochemistry
because of their history in agricultural chemistry which evolved over the years into
biochemistry. And I knew that with an average high school background, in state, I would be
admitted to the University of Wisconsin, and that I would catch up then.
Hughes: Isn t there a separate institute of biochemistry at Wisconsin?
Scheller: There s the Enzyme Institute, which is largely a school for enzymatic studies, which is mostly
biochemistry. But remember, the University of Wisconsin is a place where there are 50,000
students. There s a genetics department, a microbiology department, a biochemistry
department, enzymology, zoology, molecular biology, cell biology, and it goes on and on. It s
a huge place.
Hughes: And you were in the department of biochemistry?
Scheller: I was, which interestingly is in the school of agriculture because of the history there: The
discovery of vitamin D and, as I mentioned, the biochemistry department formally being
called agricultural chemistry.
The funniest thing I remember about that is in my freshman year being recruited to be in a
fraternity in the agriculture school, which is mostly comprised of people that were training to
be dairy farmers, [laughter] Most of the people did not grow up in the city. It was very funny
when I was invited to their fraternity house for a recruiting dinner, and I told them that I
wanted to be a biochemist. Clearly, this did not fit in with this group of people in the ag
school.
Hughes: Did you have friends who were interested in non-agricultural biochemistry?
Scheller: As friends, and certainly as colleagues in my classes, and so on, sure. I became at that time a
very, very serious student where I studied day and night for four years and learned
biochemistry.
Hughes: What attracted you to biochemistry?
Scheller: As I said, I honestly don t know. I wanted to be a scientist, a chemist, and a biochemist, even
in high school. I think what attracted me was that as a child I liked microscopes; I liked the
study of biology; I liked living things, but I also really enjoyed chemistry. I think that at a
very early age, twelve years old, thirteen years old, it emerged as an amalgamation of my
"scientific" interest. That s really the earliest that I can trace things.
Undergraduate Research
Hughes: Did you do any research as an undergraduate?
Scheller: Yes, I worked in two laboratories. As my earliest research, I worked in an oncology group,
studying the metabolism of the amino acid tryptophane in patients with bladder cancer. I then
studied in the biochemistry department in an x-ray crystallography group, which resulted in
what eventually turned out to be my third publication, because it came out after I left
Wisconsin-a publication in collaboration with some of the then graduate students at the
University of Wisconsin. 2
Hughes: Was it unusual for an undergraduate to be publishing with graduate students?
Scheller: I think it was a little bit unusual. It s not unheard of.
Hughes: Were you actually doing crystallography?
Scheller: I was doing crystallography. I was also purifying the molecules and growing the crystals,
doing molecular modeling studies.
Hughes: How were you learning these techniques?
Scheller: By working with the graduate students and the postdocs that were there. I became good
friends with them, and even actually see some of them today, which now~I don t even want to
think about it is thirty years later. They re professors at various universities and they shake
their head and think, "This is that undergraduate that worked with us."
Hughes: Did you have any particular relationship with any of the faculty members?
Scheller: I knew a variety of the faculty members. I m not sure that I was particularly close to any
individuals.
Hughes: So you didn t have a mentor at that stage?
Scheller: Not really. I think there are a lot of very dedicated teachers at the University of Wisconsin. I
thought that the classroom lecturing was generally outstanding. There were tremendous
opportunities, even at a large state school, to do individual research and an honors
undergraduate thesis. I have had a little more experience with different universities now and
can look back and say the University of Wisconsin is an absolutely terrific, first-rate
institution. I owe a lot to them for the education that I received there. Even though there are
50,000 students there, they re taught well.
2 See #3 in Scheller s bibliography in an appendix to this oral history.
Graduate Student, California Institute of Technology. 1975-1980
Richard Dickerson, Arthur Riggs, and Research on lac Represser Protein
Hughes: How much of this education were you destined to use when you moved to graduate school?
Scheller: That s an interesting question, because I think my interest in x-ray crystallography shaped the
choice of graduate school; it shaped the laboratory that I joined; and that shaped the whole rest
of my life, of course. I was interested in atomic structures and biological molecules and the
way the structures determine the function of the molecules. I had read a book by a professor
at Caltech; Richard Dickerson is his name. I don t know if his name has come up in your other
discussions, but it should.
Hughes: It hasn t, but I ve certainly seen it in the material I have on you.
Scheller: I decided that I wanted to work with him. I think I also heard a seminar that he presented at
the University of Wisconsin, so I applied to graduate school at Caltech specifically to work in
his laboratory. Again, that was really based on my undergraduate research experience and the
interest that I had developed in x-ray determination of biological structures.
Hughes: I don t imagine there were too many undergraduates who could present such a background.
Scheller: Probably not too many.
Hughes: Was Dickerson doing x-ray crystallography himself?
Scheller: Oh yes. He s a famous x-ray crystallographer. In about two months I m going to a symposium
in Los Angeles for his seventieth birthday. It will be held at the Getty Museum. It should be a
lot of fun. I m an invited speaker at this symposium, so it s a chance for me to show that I ve
made something of myself.
Hughes: Tell me about Dickerson as a personality and what it was like being in his laboratory.
Scheller: The reason I became very interested is that we had an idea that we would solve the atomic
structure of the lac represser protein bound to the operator DNA. This is a classic system in
bacteria for regulating the expression of the gene. This is actually the system that [Francois]
Jacob and [Jacques] Monod worked on, which they won the Nobel Prize for. The specific
question that we were interested in is how the represser protein binds the DNA in a specific
place. The E. coli chromosome is 4 x 10 6 nucleotides of DNA, and this protein was able to
pick out twenty-one nucleotides of that 4 x 10 6 and very specifically bind to that site and shut
off expression of the gene. We wanted to understand that recognition process at an atomic
level.
Hughes: The fact that the gene was shut off had already been worked out by Jacob and Monod?
Scheller: And others.
Hughes: And others.
Scheller: When the appropriate signal was presented in the environment, a molecule would bind to the
represser so that it would fall off the DNA, and that would then allow expression of the set of
genes. It was the way that the bacteria sensed the nutrients in the environment and regulated
their gene expression accordingly, so that they could metabolize the nutrients appropriately.
Hughes: This was a pretty hot area of science, was it not, at that time?
Scheller: It was really a very interesting area, sure.
Hughes: A lot of different laboratories were competing, were they not?
Scheller: Anything that s interesting, a lot of laboratories are usually competing.
Here s where the story gets interesting in terms of the specific connection to Genentech.
At the time we needed to isolate the protein and the DNA. The protein one could isolate; the
person, Art Riggs, who was an expert in isolating this protein worked at the City of Hope
[Medical Center], just down the freeway. I forget which [exit] number it is by now, but it s
down the freeway from Caltech. Riggs had a collaboration with Dickerson at Caltech to
isolate the protein. The problem then was that we needed the DNA, and DNA at the time was
extremely difficult to come by, especially large amounts of a very specific sequence. So
Dickerson and Riggs thought that maybe instead of isolating the DNA from a natural source,
that perhaps one could synthesize the DNA chemically in a test tube, bind it to the protein,
crystallize that complex, and then solve the atomic structure.
DNA Synthesis
Hughes: Gobind Khorana is a name that I associate with DNA synthesis. Are we talking about the
mid- 70s? Had Khorana done his work by that time?
Scheller: Khorana was working with a hundred people for years to synthesize the tRNA [transfer RNA]
gene. Even to synthesize the twenty-one base-pair DNA for the lac operon by Khorana s
method would have been extremely difficult and time consuming; and to make a strand of
DNA twenty-one [base pairs] long would be very hard and would have probably taken years.
When you re done you wouldn t get very much, etcetera. A Japanese chemist working in
Canada with a former student of Khorana s had invented a different way of synthesizing DNA;
his name was Keiichi Itakura.
Hughes: Are you going to tell me how his way was different?
Scheller: Yes. What Keiichi did was to put a protecting group, we call it, to modify the DNA by putting
a chemical entity on the phosphate of the DNA backbone so that the DNA was no longer
negatively charged. He put a parachlorophenol, was the name of the group, on the phosphate
backbone of the DNA so that it was no longer negatively charged. That meant that instead of
having to work in solution, in water, the chemistry could be done in organic solvents. Organic
chemistry was a highly developed field even then, with much better-understood properties of
the chemical components. The DNA was much easier to synthesize in organic solvents than
water. Then when you were done with the synthesis, you removed all the protecting groups
and you were left with DNA.
Hughes: So Khorana had been working in a water medium?
Scheller: Yes.
Hughes: And that had slowed him down, made it more difficult?
Scheller: Yes. Riggs and Dickerson knew about the work of Itakura, and they brought Itakura to
Caltech. And Itakura 99 percent- (I ll say "we" because I arrived at Caltech about the same
time as Itakura, within a couple of weeks of each other.) We set up although I knew nothing
about it; he did a DNA synthesis lab at Caltech. Our goal was to synthesize the lac operon
DNA. Riggs and the scientists that he was working with at the City of Hope and at Caltech
would purify the represser protein, and then we would mix them together to solve the crystal
structure. We never did that, [laughs]
Hughes: You mean you never solved the crystal structure?
Scheller: Right. But a few years ago [it was solved] by someone else. It took twenty years in between
to actually get it done. That was the idea at the time, and that s what brought Dickerson,
Riggs, Itakura, and me together. In fact, Dickerson was the nucleus of this event.
Dickerson s Laboratory
Hughes: Tell me about him and how he got to this point in his research interest.
Scheller: As I said, he s a famous x-ray crystallographer who worked at the MRC [Medical Research
Council] Laboratories with the people that invented protein crystallography. Max Perutz won
the Nobel Prize. Dickerson was a renowned chemist and crystallographer and professor at
Caltech. He s a very good teacher. He wrote textbooks. I remember one of the things that he
asked me to do one weekend was to solve all of the problems in the chemistry textbook that he
had written so that he could compare my answers to his answers to make sure that they were
right. He paid me $100 or something for that, which at the time was a huge amount of money.
Hughes: And they did match?
Scheller: They matched for the most part, I think; I don t really remember the details, but certainly they
mostly matched. I had to solve these several hundred chemistry problems though. I say now I
had to solve them because it sounds like quite a chore, but back then for $100 I was very
enthused to solve them all. [laughter]
We worked in the laboratories that were occupied by Linus Pauling when he was at
Caltech. Some of the protein models that were in some of the laboratories in the halls that I
walked up and down were actually made by Pauling and his workers. It was really a very
historic place.
Hughes: How many of you were there, aside from this group working on the lac represser?
Scheller: Other technicians and graduate students and postdocs.
Hughes: With different projects?
Scheller: Yes. Some of whom were working on this project with us. Some people were working on the
protein component as I was working on the DNA component, and others were working on
other projects.
Hughes: Why were you working on the DNA component?
Scheller: I m not sure there was a particular reason. I think because Itakura came to Caltech at about the
same time and needed help setting up the lab; it seemed like a natural thing. I know that [I
was] Keiichi Itakura s first graduate student. We became very good friends. We ve drifted
apart over the years, but at the time he was really my mentor. Dickerson was so famous that
he spent more time in the office, while we spent time in the labs, similar to what I ve been
doing for the last ten or twenty years.
Hughes: Was DNA in itself then a real focus of biochemical attention? Because it hadnt been early on
in biochemistry.
Scheller: Right.
Collaborating with Herbert Boyer to Clone lac Operator DNA
Scheller: I think the next thing that happened is very interesting and important because it s the
connection that brought Herb Boyer into the picture. It was the thought that the DNA that
Itakura made was good DNA, but it still wasn t quite enough. So we wondered-mostly Riggs,
and Itakura, and Dickerson-we wondered whether we could clone the DNA. There was a
very easy way to know if you ve cloned the lac operator DNA because if you put the binding
site of the protein into the bacteria, you would suck the protein off of the bacterial
chromosome because it would bind the plasmid that contains the synthetic DNA, and that
plasmid was present in maybe ten or twenty copies inside the bacteria. So you would suck it
off the chromosome because it would bind the plasmid DNA, and that would then turn on the
gene. You could see that by the bacteria colony turning a certain color if you gave it the right
substrate. So Riggs and Itakura gave the DNA to Boyer who had just invented the cloning
method. Beyer s group-Herb Heyneker I think in particular; I don t remember exactly who-
put Itakura s synthetic DNA into the bacteria.
8
The interesting thing about Itakura s synthetic DNA is it was twenty-one base pairs and it
had flushed ends. I wanted to put it into the EcoRl restriction enzyme site. Boyer had a piece
of synthetic DNA that was eight nucleotides long that contained the EcoRl restriction enzyme
site which he was using to study the properties of the restriction enzyme.
Hughes: Had he made the DNA?
Scheller: That was probably made the Khorana way. I m not sure who made it.
Hughes: Heyneker knew how to synthesize DNA?
Scheller: No, Heyneker was a molecular biologist.
Hughes: Well then, who was doing the synthesis?
Scheller: Boyer collaborated with someone.
That was an eight base-pair piece of DNA which was symmetric, meaning that it
hybridized to itself. Its sequences were the same reading forward and backward, so you only
had to make eight nucleotides. The lac operon was twenty-one nucleotides. It was not
symmetric, so that was forty-two nucleotides that you had to make. I would say to make forty-
two nucleotides versus eight was one thousand times harder.
What Heyneker did was to ligate the eight base-pair EcoRl sites onto Itakura s twenty-one
base-pair site, then to cut with the restriction enzyme, and then to place this piece of synthetic
DNA into the plasmid, and the plasmid into bacteria. That actually was the first cloning of
DNA made in a test tube. That was done before Khorana.
Hughes: Oh really?
Scheller: Absolutely. No doubt. It s in the historical record of the publications; it was published first.
Hughes: Do you remember the year?
Scheller: It would be referenced in the Science paper on linkers. 3 [Pause while looking for the
reference.] Then that gave rise to the idea that it would be useful to have synthetic restriction
enzyme recognition sites useful for cloning.
m
Scheller: I then synthesized the Hind EH, BamHl, and EcoRl restriction enzyme sites and showed they
were cut by the enzymes and so on. That s the 1977 paper in Science, which is hard to believe,
because now if you want a ten-base pair of DNA you just e-mail your request to your synthesis
group, and if you don t have it by the next day you re wondering what they re doing and why
it s taking so long.
3 Scheller bibliography, reference #1.
Perhaps more importantly for historical purposes, this is where Riggs, Itakura, and Boyer
got together. It only takes one more person to make Genentech.
Scheller s DNA Linkers
Hughes: Getting back to that first paper: It was more, I thought, than the fact that you made linkers
with restriction sites. It was also the fact that they had sticky ends, is that not true?
Scheller: Sure, well that s why they were put on in the first place; that was the whole point.
Hughes: What was new about what you did other than the fact that there were restriction sites?
Scheller: People had cloned pieces of DNA with sticky ends into restriction enzyme sites. The problem
was that a lot of times, probably most times as a matter of fact, the piece of DNA that you
would want to clone didn t have sticky ends. You wanted to put the sticky ends onto your
DNA so that you could clone it. That s what this [method] allowed one to do, and has in fact
been used by [Peter] Seeburg, and [Axel] Ullrich, to clone the cDNA [complementary DNA]
for insulin, clone the cDNA for growth hormone, and so on. I remember I sent out these
pieces of DNA to scientists all over the country, all over the world, to be able to use them for
their cloning experiments because there was nowhere else you could get them.
Hughes: Do you have a record of the laboratories that you sent linkers to?
Scheller: No.
Hughes: Wouldn t that be a rough profile of laboratories that were early into recombinant DNA?
Scheller: It would be some measure, sure. I know I sent them to [Mark] Ptashne and [Walter] Gilbert at
Harvard. I know I sent them to UCSF.
Hughes: Because you had originated this way of linking.
Scheller: Sure. You write a paper on just [their] synthesis-this is trivial by today s standards.
Hughes: It shows you how far the field has advanced. But there were other methods for linking pieces
of DNA, even at that time, right?
Scheller: They were less efficient; they were harder to do, and they weren t as convenient. This method
was also convenient because when you put the DNA in with a restriction enzyme site, and
then you propagate it through the bacteria, and then you isolate the plasmid, you can also cut
the DNA out again. If you put it in other ways it s much harder to retrieve.
Hughes: So it became the preferred method?
Scheller: A preferred method, sure.
10
Hughes: I m thinking of the Stanford group around Paul Berg which was recombining DNA in different
ways. There was the tailing method, for example.
Scheller: The problem with the tailing method is it didn t allow you to cut the DNA back out afterwards.
No Memory of the Introduction of Recombinant DNA Technology
Hughes: What about your early memories of the Cohen and Boyer work on recombinant DNA? Do
you remember when you first began to hear about it, and how?
Scheller: Not really. When I moved to graduate school [1975] it pretty much had become quite
routinely used, although the methods were very primitive compared to what we do now. The
Cohen-Boyer work, when was that done?
Hughes: Three papers were published in 1973 and 74.
Scheller: I was an undergraduate then, and that kind of thing didn t really enter my world until graduate
school. In graduate school it was something that was being pretty commonly done. I just
don t remember; I was not a practicing scientist; I was a classroom scientist when the work
was done. And I was studying x-ray crystallography, not molecular biology, so it didn t really
rock my world, [laughs]
Hughes: Nonetheless, when you arrived at Caltech in 1975, this technique was at most two years old,
and yet it was an accepted routine for people doing biochemistry or molecular biology?
Nobody thought much about it? It was just another technique?
Scheller: Yes. As I say, it was very primitive compared to the way we practice it now. Just another
technique. Every lab at Caltech that wanted to used recombinant DNA, and that was many,
many, many, many laboratories.
Dickerson, Riggs, and Keiichi Itakura
Hughes: You haven t told me very much about personalities. Start with Dickerson if you don t mind.
What was he like? How would you characterize him?
Scheller: Dickerson was a very big-picture guy, a little bit aloof I would say.
Hughes: British?
Scheller: No.
Hughes: You said MRC-
11
Scheller: He was a postdoctoral student there. I m not sure where he was a graduate student. He really
was not as interested in the details of the experiments as others. He s a very good
undergraduate teacher and lecturer in chemistry. Many of the undergraduate students at
Caltech took freshman chemistry from Dickerson. [He was] interested in organizing big
science projects-although they wouldn t be big by today s standards-like trying to do this lac
operon represser crystal structure, which involved Riggs and bringing Itakura from Canada,
and so on.
Hughes: He facilitated that?
Scheller: Yes.
Hughes: And he planned the general orientation of the research?
Scheller: Yes. I think that he and Art Riggs planned the research. Art Riggs was much more
technically oriented, had more experience with this specific protein biochemistry, not with the
x-ray crystallography. I think that Art Riggs was conservative scientifically and very precise
and rigorous.
Hughes: Meaning that Dickerson wasn t?
Scheller: Well, Dickerson didn t even deal with things at that level.
The person that we haven t talked about is Keiichi Itakura. I worked side by side with
Keiichi in the laboratory. He s really the one that taught me how to synthesize DNA, and he s
the one I worked closest with. I was twenty-two or something like that. I was very, very
impressionable in all ways.
Hughes: Tell me about Itakura.
Scheller: He was a very fun guy. He didn t speak very good English. I probably communicated with
him more than anyone else just because we were standing or sitting next to each other all day,
every day. He had a very lovely wife and a nice family. He worked extremely hard. I think
that he had lived in Canada for a number of years but was still very Japanese in a number of
his mannerisms and ways and, as I said, not particularly easy to communicate with. But he
was a friend of mine.
I remember that I didn t have a car at the time so I borrowed his car one evening to go out
on a date. I think he was quite nervous in loaning it to me, making sure that I brought it back.
He lived close enough to me that I could just return it and walk home to my house from his
house. It s one of those things you just remember as a funny event.
Applying Recombinant DNA to Gene Expression in Animals
Hughes: Should we skip to the research you did at Caltech?
12
Scheller: Since recombinant DNA was becoming very widely used by anyone who wanted to do the
technique, I thought that one of the most intriguing problems in all of science was, and still is,
how a sequence of DNA is read out and interpreted to give an animal. There was a lot of
excitement that we might be able to understand how gene expression is controlled in animals
in the same way we understood how lac operon was turned on and off in a bacterium. And if
you could understand that in animals, that would really be the key to how differential sets of
genes were expressed in different cells and throughout development to give rise to adult
organisms.
There were ways, but no real promising ways, to study that before recombinant DNA
came along, because the genetics of animals is very tedious, unlike [that of] bacteria. There
was no way to get the DNA. You could make DNA from an animal; that was fine. But then
you had 3 x 10 9 nucleotides of DNA in a test tube; what would you do with it? The notion
that you could take the DNA of an animal and cut it up into little pieces and use recombinant
DNA to clone the DNA to isolate specific sequences of animal DNA then meant that you
could study that piece of animal DNA, perhaps figure out how it worked at the same level of
understanding as the lac operon. That was a big deal. It was very, very exciting.
Hughes: How would a researcher select the specific segment of DNA that he chose to work on?
Scheller: That was a problem at the time. Sometimes, for instance, you could start with the RNA, and
make the RNA into DNA, and then put linkers on the end, and then clone it. If you worked
with a blood cell, almost all of the RNA in the blood cell encoded globin (the red part of our
blood). So you could get the globin cDNA just by looking at any random clone made from
blood cells because most of them would be that sequence. It was primitive kinds of things like
that, that you had to use in order to get a specific piece of DNA. Other people studied random
pieces of DNA; a piece of DNA from an animal is bound to be important for something.
Hughes: If you had a random sequence of nucleotides, how were you going to link them up with
function?
Scheller: People had all sorts of ideas. As a matter of fact, it rums out that it s still a very hotly
investigated area of science.
Hughes: You re thinking of the Human Genome Project?
Scheller: Well, I was thinking: Do we know now how sperm and an egg come together and read out the
DNA to make an animal? No. We know a lot more than we knew twenty years ago, but it s
not as simple as the lac operon. People thought if you had the DNA, for example, that you
could look for proteins like the lac represser that bound to the animal DNA, and say, "Stop!
There s a repressor-like protein." People thought if there were ten genes turned on in a
particular cell, like a liver cell, all the liver genes might have a particular DNA sequence in
front of them that might say, "This means you have a liver gene." The piece of DNA would be
a binding site for a protein or a transcription factor that would turn on the DNA in liver. So if
you just looked at the DNA from ten liver genes, and they all had nothing in common except
this particular region, then that region would then likely be important. There were a lot of
those kinds of ideas that we were all sure would work out much more quickly than they did.
This is still an issue, as I said, that people are investigating and doubt. But that was an
13
extremely exciting time because, as I said, recombinant DNA was being widely utilized to
study whatever particular problem you wanted to study.
In 77 there were cDNA libraries being made, so copies of the mRNA [messenger RNA]
from different cells were being put into bacteria. Then genome libraries were being made so
that the DNA in the nucleus was being cut up into pieces and cloned into bacteria. I know that
there were libraries from rabbit, Drosophila, sea urchin, mouse. These were the labs of
Norman Davidson (Drosophila), Tom Maniatis (rabbit) who was then a professor at Caltech,
Leroy Hood (mouse), Eric Davidson (sea urchin). These were some of the first whole genome
libraries that were made.
Hughes: By what time?
Scheller: Seventy-seven. One could then go into the libraries and find the genes.
Hughes: Were they making these libraries available to anybody that wanted them?
Scheller: Probably; I m not sure. It wasn t so easy to copy the libraries back then.
Hughes: Why was that?
Scheller: As you propagate them, they change their representation; some clones grow a little better than
others. I don t really remember. I presume they were made available for other people.
The Recombinant DNA Controversy
Hughes: The recombinant DNA controversy was going on in the mid to late 1970. How much were
you aware of it, and did it shape the way you were doing your science?
Scheller: I was aware of it because Tom Maniatis moved to Caltech specifically because of some issues
revolving around this controversy. He moved to Caltech, I believe, in part because some of
the controversy in Cambridge, Massachusetts, where he was not able to do all of his work at
Harvard. Perhaps that was one of the reasons-you would have to ask him-that he moved to
Caltech. At the same time, [Robert]- Sinsheimer was the former chairman of the department of
biology at Caltech and was actively involved in the controversy.
Hughes: On the other side, right?
Scheller: That s right.
Hughes: What did that mean for scientists working in recombinant DNA?
Scheller: We didn t really take it very seriously. I think that people pretty much believed that of course
you wouldn t want to propagate DNA from a very active or dangerous virus, but that the work
that we were doing was relatively harmless. We were careful to dispose of materials
14
appropriately and to wear gloves, and so on. There was no real concern by most people that
anything we were doing was dangerous. I think the largest concern was that there would be
some kind of moratorium to keep us from doing our work.
Hughes: And there was.
Scheller: There was-for certain kinds of work: cloning from tumors or cancer cells, cloning of certain
kinds of viruses. The moratorium, as a whole, was really quite short. It really didn t affect
anybody very much. It was also voluntary, if I remember [correctly]. There was no
enforcement really.
Hughes: It was a scientist-imposed moratorium and where was the regulation? There was no
governmental regulation.
Scheller: I think that it was voluntary. Some people paid attention and others just totally ignored it. It s
not like the police were going to come or anything.
Hughes: Were you aware of the political machinations of that period, or were you just doing your
science?
Scheller: I was aware of it and thought it was all absurd.
Hughes: How could you be sure?
Scheller: I can t be sure, but it seemed that we understood the biology better than anyone else in the
world since we were the ones that were working with it, inventing it, modifying it, and so on.
Our best technical assessment was that it was not dangerous. One can t be sure. Remember, I
was twenty-two or three or four, or whatever I was; I was immortal then, of course.
Hughes: Yes, exactly, [laughter] It s not an age where youVe looking for reasons not to.
Scheller: That s right. Just do it!
Hughes: The NIH guidelines came into force in 1976. Was there much notice paid in the laboratory?
Scheller: I m sure we abided by the guidelines, but that basically just meant having a room set up in an
appropriate way for the kinds of work that were going on. I worked mostly with sea urchins
which are not mammals. They required a fairly low biosecurity level of containment, which
was basically a room that had somewhat limited access where you autoclave things when you
are done. It really wasn t much of a constraint.
I think it was good that the scientists thought about it; I think it leant a legitimacy to the
endeavor. It assured people that scientists were thinking about potential dangers. It did lead
to the use of bacterial strains and bacterial virus strains that are weakened compared to those
that live in the wild, so that even if they did "escape" from the laboratory they wouldn t
survive. I think it was a good thing to do on the same kinds of strains.
Hughes: Were you using them as well?
15
Scheller: Sure.
Hughes: Were they hard to work with?
Scheller: Not particularly. We could pamper them in the laboratory so that they would be very happy
growing there; they wouldn t have to compete with all those tough bacteria that live out in the
wild.
Hughes: The picture you paint is: Yes, there was an awareness of the political situation, but all these
issues were not having a tremendous impact on what you were doing. You pretty much
carried on as you had before the recombinant DNA issue arose, within certain limits.
Scheller: "Tremendous" is an overstatement. It had very, very little effect on us doing the work in the
laboratory. Very little effect.
Hughes: Do you remember the controversy having any effect on the problems that you chose?
Scheller: No. We followed the interesting scientific problems. As I said, I think there was some fear
that there might be some rules imposed that would get in our way, but there never were.
Hughes: And there never was federal legislation, for many reasons. One of the reasons was that by the
late 70s the commercial potential of recombinant DNA was becoming more obvious;
recombinant DNA was seen as a technology that might rescue the flagging American
economy.
Scheller: I m not sure that that really played a role. Maybe you know differently; you study this. But
I m not sure it played a tremendous role in influencing safety guidelines. I think that if
scientists honestly believed that [recombinant DNA technology] was unsafe, even if it was
possible to make a lot of money, they would have imposed guidelines. I think the vast
majority of scientists honestly believed that with relatively simple precautions this technology
was not dangerous!
Richard Sinsheimer s Concern about Recombinant DNA
Hughes: Do you have any insight into why Sinsheimer questioned the use of recombinant DNA?
Scheller: I didn t really know him very well. He was chairman of the department [Division of Biology]
at Caltech before I arrived. As a graduate student, I really didnt interact with him very much.
He was thought of by us as someone on the other side of this debate, but I never really
interacted with him so I don t really know.
Hughes: It didn t cause a schism in the department?
Scheller: He moved to Santa Cruz.
16
Hughes: He became chancellor.
Scheller: I don t remember exactly when, but he left Caltech and became chancellor, and then there was
no schism in the department because he wasn t there!
Hughes: But when he was there, there could have been hesitation, or at least more care, about how one
used recombinant DNA. If you had a critic who happened to be chairman of the department-
Scheller: But he was not chair at the time. He was formerly chair of the department. I think Lee
[Leroy] Hood was chair of the department at the time and was one of the aggressive users of
recombinant DNA. Since Sinsheimer was former chair, he was probably entertaining other
administrative positions where he wouldn t run a laboratory anymore, and then soon moved
to Santa Cruz. I have a memory of him being on the other side of the debate, but nothing
really very specific beyond that.
Interacting with Leroy Hood s Laboratory
Hughes: Did you have any specific ties with Lee Hood or his laboratory group?
Scheller: Well, some of his students were in the laboratory next to mine. One of the students in the lab
that was next to mine is now on the faculty at Stanford; we were both on the faculty there for
the last twenty years before I moved here. I interacted with his students routinely. We shared
reagents and ideas and things.
Hughes: Was it a pretty communal place?
Scheller: Absolutely, absolutely. The techniques and reagents were shared. At the time, we also made
things like enzymes. They were quite expensive back then, so we had a laboratory that would
purify restriction enzymes for us. The technician worked on purifying the enzymes and would
make $200,000 worth by the catalogue price in a couple of weeks and would distribute them
to the different laboratories. We conserved on money by making them ourselves. There were
only a few different restriction enzymes that were known back then. Hood s students also
rotated in making radioactive ATP; one person would do that every week and then share it
with the whole group.
Hughes: You being one of those students?
Scheller: Sure. We went over to the physics department and used a laboratory specific for radioactivity.
It was a very, very, very communal feeling back then because we really weren t competing
with each other. We were using different experimental organisms to ask different questions
but using common techniques. So we shared the techniques, and our specific experiments
were not in any way competitive with each other. It may have been the perfect kind of
atmosphere to collaborate or cooperate, whatever the case may be.
17
The Sea Urchin as Experimental Organism
Hughes: You mentioned that you took up research with the sea urchin. I m assuming the overall goal
was to get a better handle on how higher organisms developed, as opposed to E. coli, which
you had been working with first.
Scheller: Yes.
Hughes: Were other people working in non-bacterial organisms?
Scheller: Well, sure. People worked in C. elegans, and Drosophila, and sea urchins, and rice-
Hughes: I meant right in your lab group.
Scheller: Eric Davidson s laboratory group focused on the sea urchin. It is quite common for a
laboratory group to focus on a specific experimental organism. We studied the sea urchin
because we were particularly interested in early embryonic development, meaning one cell
going to two, four, eight blastula-gastrula stages. Of course in a mouse or a human that s very
hard to study because in a mouse, for example, you might have six or so embryos that are
fertilized at a time. I don t know if you ve ever had uni. That s sea urchin gonad; it s a sushi
ingredient.
Hughes: I ve heard of it.
Scheller: I love uni. If you inject the sea urchin with the appropriate salt solution it will deposit its eggs
and it can be millions of eggs. It s the eggs that sperm will fertilize, and they go through
development in a relatively synchronous way. It s possible to obtain many hundreds of
thousands and millions of embryos from the sea urchin, versus six from a mouse, which would
not be very much material to work with. So that was the reason for studying sea urchins.
Scheller s Research on Embryonic Development
Hughes: Tell me what you were interested in.
Scheller: The question was the issue that I raised earlier: How does the linear sequence of the DNA give
rise to a complex, three-dimensional, thinking, breathing, adult organism?
Hughes: Nice, narrow question.
Scheller: I believe sea urchins think, not of course the same way we do. In particular our focus was on
those very early stages of development.
Hughes: So you were narrowing it down, because that seems to be a tremendously broad question.
18
Scheller: Sure. The idea was that we could study the expression and the roles of specific DNA
sequences that we isolated through recombinant DNA methods during these early stages of
development.
Some of the people in Eric Davidson s lab were particularly interested in DNA sequences
that are repeated many times in the genome. Some pieces of DNA are present only one time
in the nucleus, and others maybe a hundred times or a thousand times. There was an idea, as I
mentioned before, that these repeated sequences might be landmarks in the DNA that are
important in determining the expression pattern of the DNA. We isolated these repeated
sequences using some tricks and were studying the way they were expressed and the way they
were organized. That was part of the work that I did.
Scheller s Research on the Actin Genes
Scheller: I also studied this specific set of genes called the actin genes; [they are genes] for a component
of the cytoskeleton. They is a family of these genes, I forget how many, maybe five or ten
related genes that turn on and off in specific cells in specific patterns. I believe Eric
Davidson s laboratory group at Caltech still studies these actin genes and is still trying to
answer the same question that we set out to answer years ago about what controls their
expression.
Postdoctoral Fellow in Neuroscience, Columbia, 1981-1982
Reductionism
Hughes: One paper that I looked at while I was waiting for you was a 1 983 paper in which you were
finding that one gene, the gene encoding egg-laying hormone 4
Scheller: That s when I left Caltech to go to my postdoctoral studies at Columbia. I became interested
in trying to understand, at a biochemical or a molecular level, why it is that animals do the
things that they do, their behavior. Of course if you re a biochemist you re a reductionist,
which means that we should be able to explain all aspects of life-not only how an animal
developsthrough an understanding of cells and molecules. But we should also be able to
understand behavior through an understanding of cells and molecules.
Hughes: And you believe this?
Scheller: Sure, what else is there? It s your brain after all. Your brain is made of cells and molecules.
4 See #14 in Scheller bibliography in appendix.
Hughes:
19
Unless you believe in some spirit or life force that tells you what to do, something that a
scientist would have trouble with, it s really all we have. So of course I believe that.
Do you agree that it s not quite as simple as it was originally pictured to be in the Central
Dogma?
Scheller: Nothing is as simple as I shouldn t say nothing is as simple. Things in science tend to go
through phases where you think it will be simple; you find out it s complicated, but then once
you understand it, it seems simple again. I m not sure what stage we re at in life science right
now. I think, actually, we re at the complicated stage right now. [laughter]
Eric Kandel
Scheller: The famous scientist at Columbia who won the Nobel Prize last year, Eric Kandel, had been
one of the early scientists who thought that if you could understand behavior in terms of the
neural circuitry, you could understand the neurons that mediated the behavior, and then you
could modify that behavior with experience, and then study the ways cells had changed. You
could understand where the memory was which resulted in the change of the behavior. We, as
neuroscientists, still believe that s the case. Kandel s training was as a psychiatrist but a very
biologically oriented psychiatrist.
One of the things the animal (which was a marine snail, Aplysid) that he studied does is to
lay eggs in a very stereotypic pattern. All of the animals lay their eggs in the same way: the
egg string is excreted from the back. They hold the egg string in their mouth, and they move
their head back and forth in a line it could be a long string of eggs if it was in linear
sequence; it could be several meters. They wind it into a coil and deposit it as a sticky mass
on the side of the tank, or in the wild maybe on a rock or a leaf or what have you! All of the
animals lay eggs that way. They re born knowing how to do it; they don t have to learn how to
lay eggs that way. This innate behavior somehow has to be encoded in their DNA, in their
nerve cells, and their chemical communication between the nerve cells.
The advantage of studying this animal is not only that they have relatively simple
behaviors the snail doesn t do a whole heck of a lot: it eats and has sex, lays eggs, and that s
pretty much it-but that there are only about 20,000 neurons in the animal. Some of the cells
are extremely large; they re up to a millimeter in diameter, so you can see a single cell with
your naked eye; it s tiny but you can see it. The makes it, of course, easier to do
electrophysiological studies or even biochemical studies, because of the large size, relatively
small number, and the stereotypic organization of the cells.
Scheller Clones the Gene for Egg-laying Hormone
Scheller: We knew that if you extracted part of the nervous system just cut out a set of cells called the
20
bag cell neurons-and you ground them up, and you injected them into a second animal, that
the animal would go through its stereotyped egg-laying behavior. That said, there had to be a
chemical substance in those cells that triggered the behavior. It was known that this chemical
substance-at least one of the chemical substances-was a short protein, a peptide, called the
egg-laying hormone. So I set out to clone the gene encoding that hormone, and through
understanding the organization of the gene was able to understand that the gene encodes more
than one chemical substance that s important in producing the behavior.
We hypothesized that it s the concerted action of the set of these substances that are
secreted from these neurons that produced the behavior. We understood then, as the years
went on, how this protein is made, how the different chemical substances are packaged, and
how the neural activity results in the secretion of these different substances, the physiological
activities, and so on.
Hughes: Was it fairly well known then that a gene could express different proteins?
Scheller: Well, this gene made one protein, but then the protein, as it moved through the cell, was cut up
into different pieces, and the different pieces were utilized differently.
Hughes: Was that known? Were there other organisms-?
Scheller: The other pieces of this gene were not known. It sort of was a hallmark of what was to come
in molecular neurobiology, as in all areas of cell biology, that it s easier to work with DNA,
and to understand cellular properties and molecular properties by manipulating the molecules
through the DNA. That was really what we had done here in the nervous system, which I
think showed people-again, something that seems obvious nowthat the way to dissect the
brain and the way to dissect things like behaviors at the molecular level was to use this great
set of technologies of molecular biology to go in and pick apart processes.
Hughes: Because the technology at that stage was better for working with the DNA than it was with the
proteins?
Scheller: Yes. DNA has four building blocks; it s a very sturdy molecule. You can t clone a protein. A
protein doesn t reproduce itself; DNA reproduces itself.
Hughes: And proteins can have folding problems.
Scheller: Sure. One of the commonly accepted ways of studying all biological processes, including
neurobiology, of course is through molecular biology. Back then, for a psychiatrist to think
about DNA, and for a molecular biologist to think about behavior, that was the neat
connection that was made.
Hughes: So you were calling yourself a molecular biologist by the time you got to Columbia?
Scheller: Yes, and then at Columbia a molecular neurobiologist.
Hughes: When did you become a molecular biologist?
21
Scheller: At Caltech.
Hughes: Because you were more and more focused on DNA?
Scheller: Sure, and I think that people use "molecular genetics," meaning gene cloning, interchangeable
with "molecular biology." Molecular biology really includes biochemistry and non-DNA
things, but, as I said, I think we probably agree that molecular biology really means to most
people gene cloning.
Choosing Columbia for a Postdoc
Hughes: We dropped you at Columbia without explaining why you wanted to go there for your second
postdoc.
Scheller: Although my first postdoc didn t really count.
Hughes: Why do you say that?
Scheller: Because I stayed in the same lab. I graduated so that I could get that out of the way, and then I
could think about what I wanted to do and where I wanted to go. While I was thinking about
that I d be making a little more money; I d be finishing up some projects. I know it s on my
CV as a postdoc, but I didn t really think of it as an official postdoc, really just an extension of
graduate school where I was getting paid a little bit more.
Hughes: Nobody said well, to get more experience you should graduate and find another laboratory?
Scheller: I m sure that my advisor, Eric Davidson, would have been thrilled if I wanted to stay, but I m
sure that he would have advised me that it would be best for my career if I moved somewhere
else. As I say, since this was planned to be relatively short-it really was just a bridging
period-I don t think anybody thought very much about it.
Hughes: Why Columbia?
Scheller: Richard Axel is the person that I worked with along with Kandel. Axel is a molecular
biologist and Kandel a neuroscientist. Axel had visited Caltech and presented some seminars,
and I admired his work; I admired his personality, and it was for that reason. I had been
exposed to him and his work through seeing him present seminars and reading his papers and
so on.
Hughes: Did you go with a specific project in mind?
Scheller: Yes. Which is not the one that I did. [laughter]
Hughes: Well, tell me that story.
22
Scheller: I don t even remember what my specific project was, probably to work on some aspect of gene
expression. Axel had been sitting next to Eric Kandel on an university committee both
prominent professors at Columbia medical school. They began talking with each other and
decided that they should collaborate somehow, but they didn t really know how. It was at that
time that an issue of Scientific American on the brain came out just as I was leaving. I read
that issue of Scientific American and became very interested in the brain.
Hughes: Had one of them written an article?
Scheller: No. This issue was written by several different people; Francis Crick was one of the people
that wrote an article. So when I arrived at Columbia, Richard Axel and I began to talk about
what I would really do. He mentioned that he had met Eric Kandel, and that he was a
neuroscientist, and I very quickly became interested in that and went and talked to Kandel. It
was a fantastic experience, really, because at the time Kandel did not really know what the
gene was by the modern definition, and he certainly didn t know what recombinant DNA was,
and so on. He was a neuroscientist trained as a psychiatrist. Richard Axel had never even
seen an Aplysia, the organism that Kandel worked on, and Axel didn t know anything about
neuroscience. They had very complementary techniques, and I was the person in the middle.
It was terrific.
Interacting with Eric Kandel
Scheller: One of the great experiences in my life was Eric Kandel, last year s Nobel Laureate, teaching
me neurobiology in his office, one on one; and I taught him molecular biology, one on one.
So we taught each other what we knew about our fields. I think it served us both well.
Hughes: But your project was your project? He was somewhat at a distance?
Scheller: The question then was what to do. It was fine to say here s a molecular biologist, here s a
neurobiologist, here s a kid in the middle; you still had to figure out what really you would do.
I thought that I would make a recombinant DNA library of the genome of Aplysia, and in the
meantime I would try to figure out what to do.
I was getting help dissecting the sperm duct from the animal in order to make the DNA
from the sperm, from the germ line, and someone else was using other parts of the animal.
Somebody was cutting out certain neurons, and I said, "What are those?" And the person said
to me, "Well those are the bag cell neurons." And I said, "Okay, what do they do?" And the
person said, "They govern the egg-laying behavior." I said, "Well, that s interesting." I m
thinking I m a molecular biologist so the word "behavior" just intrigued the heck out of me. I
said, "How do they do that?" And the person said, "We don t really know except that they
secrete peptide hormones." That struck me as interesting because pepride means chains of
amino acids, which means there must be genes for these. I said, "What do they know about
these hormones?" And he said, "Not very much. They know the protein sequence."
##
23
Scheller: Remember, I said before that the cell makes a large amount of one particular thing. Then it
can be relatively easy to isolate the gene. Well, there weren t very many of these cells, maybe
a few hundred per animal, fifty microns in diameter. So from relatively few animals I could
obtain enough radioactive cDNA that I could then screen the genome library and find the
pieces of DNA in the genome that encoded the gene for the hormone. For a well-trained
molecular biologist this was a breeze.
Hughes: And you did do that very fast?
Scheller: Yes. We published two Cell papers and a Science paper in a year and a half. 5 Then I left. I
often look back and wonder where I would be if that scientist wasn t dissecting those cells. He
heard we were going to have some big animals because [we were] getting sperm to do the
recombinant DNA, and he wanted to use some other parts of the animal, and I just happened
to ask him, "What are those?" Where would this have ended up if I hadn t asked that
question? But I did.
5 #13, 14, & 17 in Scheller bibliography.
24
H FACULTY MEMBER, STANFORD, 1982-2000
Assistant Professor, Department of Biological Sciences
Deciding on Stanford
Scheller: I think then what happened happened a little fast. They wanted me to join the faculty at
Columbia. I was very honored by that. But in the same way that I think it s a good idea to
move away when you do a postdoc from the place where you ve done your undergraduate
work, to move away from where you do your postdoc is also important so that you can strike
out on your own. And since they had offered me a job at Columbia, I thought that I should
look for jobs other places in the country, and if I couldn t get one anywhere else then I would
stay at Columbia. It wasn t that I didn t like the people there; it s just that I really felt very
strongly that I needed to strike out on my own and was fortunate enough to get a position at
Stanford, which is where I moved.
Hughes: Were you offered any other positions?
Scheller: Also at MIT.
Hughes: And why did you choose Stanford?
Scheller: I wanted to move back to California. I like California; I had lived in southern California; I had
visited northern California. I didn t mention this: One of the first things I did when I moved to
California from Wisconsin was to fly up to San Francisco. I think I delivered some linkers to
the UCSF group and then hitchhiked from San Francisco to Los Angeles, camping at Big Sur
for a few days, and so on. I had very fond memories. That s when I was probably first
exposed to poison oak, which I m very allergic to now. Also I had very fond memories of
northern California.
Hughes: Did you have any particular connections with Stanford?
Scheller: No, but certainly my former mentors at Caltech and at Columbia knew people at Stanford and
were very supportive of my getting a position there. So I came out and interviewed, and one
thing led to another, and I ended up spending almost twenty years there.
25
Hughes: Your position was first on the general campus, as opposed to the medical school, in the
department of biology.
Scheller: At first. The work that I did on the marine snail in neuroscience fit in with the kind of vacancy
that they had there. Also, both Davidson at Caltech and Axel at Columbia had very close ties
to the chairman of the department at Stanford then, who was Robert Schimke, also a
prominent molecular biologist. Certainly, I think those kinds of connections speak volumes
for getting your foot in the door. Of course you have to come and perform.
Corey Goodman as Colleague in Neurobiology
Hughes: Was Schimke a neurobiologist?
Scheller: No, but there was another scientist there who was a young star in the department at the time
and a more classical neuroscientist then; Corey Goodman was his name. He was interested in
having a colleague in the department that was a molecular neurobiologist. He felt that
neurobiology was the future of biology because that s what he did. He thought that we could
share techniques and collaborate, and so on. So that would be the kind of colleague that he
would like to have, both for the good of the department and for the good of his own work.
Hughes: He wasn t a molecular biologist?
Scheller: No. He was a more classically trained neuroscientist. He used morphological techniques-
microscopy, electron microscopy, and electrophysiology~to study the development of the
nervous system, in particular how the complex circuitry, the wiring of the brain, arises. He
had defined that in classical systems like the grasshopper but then wanted to study this at a
more biochemical and molecular level, using fruit flies and recombinant DNA, and so on.
When we met, he was merely thinking about making the transition from the more cellular
studies to genetic and molecular work. I hit it off scientifically and personally with Goodman
and Schimke and other people in the department and accepted the job there.
Hughes: Did they have other people that had the skills that you did, with the heavy background in
molecular biology, or was that what they wanted?
Scheller: There were other people there: Schimke himself, Charles Yanofsky was in that department
(one of the fathers of molecular biology), and Alan Campbell who studied recombination in
bacterial viruses, phage. So .there certainly was a strong group of molecular biologists there. I
suppose you would have to ask them, but I didn t think that they had ever dreamed of studying
the nervous system with molecular biology.
Hughes: Because it seemed so complicated?
Scheller: It also just wasn t what they worked on.
Hughes: So you were bringing a new interest to the department.
26
Scheller: Sure. The way I had applied molecular biology was novel. I think everyone in the department
recognized that this novel way of applying molecular biology would result in a lot of
interesting discoveries over the years. That s the kind of person and the kind of research
program that they would like to have in the department.
Hughes: The novelty being the behavioral aspect?
Scheller: The behavior and the analysis of the behavior at the level of genes, and molecules, and cells.
Hughes: Was there anybody else anywhere doing that kind of research?
Scheller: I m not sure. I certainly don t think there was anybody that was talking about it so explicitly.
Continuing Research on Molecular Development in Aplysia
Scheller: I continued the work on genes and cells and behavior for several years at Stanford, moving on
to other neurons. We were able to dissect individual nerve cells, the bag cells that were
clusters of maybe fifty cells or so. I had to get a game permit. We would go to the Elkorn
Slough south of San Francisco; we would collect Aplysia after they had laid their eggs so that
there would be a new generation. They are annual organisms, so they were destined to die
anyway after laying their eggs. We would bring them back to Stanford and dissect the nervous
system, pin it in a dish, and people would dissect the individual nerve cells and call out that
they have an R2, or an R14, or an LI 1 . Someone else would come with a tube and place the
one individual cell in the tube so that by the end of the day we would have a set of twenty
tubes, and in each tube would be 200 individually dissected nerve cells. We could then
characterize the genes that were expressed in those specific cells. Coming back to what I
mentioned earlier, we were able to do that because the cells were large enough. We had to use
microscopes, but you could relatively easily dissect them and work with them.
Hughes: Doesn t this take tremendous dexterity?
Scheller: I don t really know; the students did that. I got the dirty work; I had to pin the animals down
and open them up and dissect their brain. Then the students would do the individual
dissections. So I had to roll up my sleeves and do the heavy-lifting work. It was fun. We had
pizza for lunch and then got back to it. It was a tremendous group effort to do that because we
didn t maintain the animals. We would collect hundreds of them in the morning, drive back to
Stanford, dissect the cells, and be finished by the end of the day. This was a long day, but you
basically had to do it all in one day.
Hughes: How often did this happen?
Scheller: This would happen periodically, a few times a year, and then we had 200 of twenty different
cells, all in the tubes. Studies of those then would take weeks and months and years. We
would clone the genes for the neuropeptides that were expressed in the cells and then try to
27
understand what those genes did--how they functioned in other aspects of the animal s
behavior.
Hughes: These were graduate students and medical students?
Scheller: These were graduate students and postdocs and M.D./Ph.D. students (the students involved in
getting both degrees). There were probably a few medical students involved.
Hughes: I asked that question because one of the emphases of Stanford s medical school curriculum at
one stage was to get students into basic science laboratories.
Scheller: That s still the case. At Stanford, in particular, many medical students take five years to get
their M.D. and spend a year doing research. Many times the medical students really don t
have the amount of time to put in to do a sophisticated, in depth, research project that would
take three, four, five years. That s of course a generalization; it s not necessarily true for any
individual. But it s hard to go through medical school and do research at the same time, which
is why we have a M.D./Ph.D. program at Stanford where you do two years of medical school,
three or four years as a Ph.D., and then your last two years of medical school, which are
mostly spent in the clinic.
Department of Molecular & Cellular Physiology ( 1990-1993) and Howard Hughes
Investigator (1990-1994), Stanford University Medical Center
[Interview 2: September, 21 2001] ##
The New Appointments
Hughes: You were in the department of biological sciences, and by 1990 you had moved over to the
department of molecular and cellular physiology. Is there a story there?
Scheller: An age-old story-money, [laughter] The Howard Hughes Medical Institute had funded
construction of the Beckman Center at Stanford, and the Beckman Center housed two new
departments that were endowed with Howard Hughes professor positions. I had been recruited
to be on the faculty at some other universities that were offering me Hughes positions, as we
called them, which amounted to about a million dollars a year for your research. Of course I
was very attracted. I think in part to retain me on the faculty at Stanford I was offered a
Hughes position.
At the time these positions had to be affiliated with a medical school due to the
complicated organization of the Howard Hughes Medical Institute. So I left biological
sciences, moved across the street, and became a Hughes professor in the physiology
department. I maintained an affiliate position with biological sciences and remained close to a
number of the faculty there, such as my wife Susan McConnell. [laughs] I m still close to a
Hughes:
28
number of the people in biology, which really gave me my start at Stanford. In a way, that s
why I say "for the money."
Did it make any difference that you were now in the medical school in terms of what kind of
research you were doing or in any other way?
Scheller: Not really. I don t think it changed a lot. I had begun studying membrane trafficking and
synaptic transmission and the mechanisms of membrane fusion while I was in biological
sciences. I have to say that the money made a big difference. It allowed me to recruit more
people. It allowed me to take more chances, to do experiments that I might not have otherwise
done because I had to rely on more conservative routes for funding my work. In a way it s sad
but true that the money really did make a difference in the research that I was able to do. The
department I was in didn t matter as much.
Hughes: I was wondering about changes in facility interactions, but of course if you were in biological
sciences right across the road that wouldn t have made a big difference.
Scheller: I think it probably did affect things in ways that if I thought real long and hard I could come
up with. The people you run into in the hallways are the people you exchange most ideas with
which do affect the work, specific experiments in particular, that you end up doing, but often
not in ways that are so easy to pinpoint. I think the point is, both environments at Stanford
were outstanding, and I enjoyed both of them.
The major difference is that the physiology department was focused on issues of
neurobiology and synaptic transmission. There were eight faculty, and everybody worked on
that. And that was good; everybody lived and breathed that science. It was stimulating. In
biology there were thirty or forty faculty members, and they studied everything from bacterial
viruses to human-population biology and ecology. It was a much more diverse department, so
the interactions there were fun in that it often stimulated you to think about things outside of
your field. But the interactions were not as stimulating for thinking deeply inside your own
field. Those were the major differences.
Scheller s Wide-ranging Interests
Hughes: I talked briefly with Professor [Charles] Yanofsky when I knew I was going to be talking with
you. He admitted that he didn t remember too much about the ins and outs of your research,
but he did remember seeing you often at seminars on a wide range of topics. Is it characteristic
of you to have broad interests?
Scheller: Sure. When I was a student at Caltech, it was possible to understand pretty much everything
that was going on in biology. To even say that to a student nowadays would flabbergast them
because there s so much going on. I felt as though twenty-five years ago I knew everything
about what was going on, and I ve tried to maintain that knowledge as much as possible in the
intervening years. Although of course it s become impossible; it s still fun to try.
29
Corporate Consultations and Comparisons of Academic and Industry Science
Hughes: Were you in some way, either conceptually or by arrangements, maintaining connections with
the commercial aspect of the science?
Scheller: I think you re going to be a little disappointed there, [laughter] Not very much. I consulted
for a few companies, and I mostly did it for the money. My salary at Stanford was comfortable
but it certainly wasn t lavish. Stock options and $1500 or $2000 a day consulting fees were
extremely attractive.
To be honest with you, I wasn t particularly fascinated with the science that was going on
in industry. I was more fascinated by the cultural differences, the ways that decisions were
made, the factors that were taken into consideration in making a decision. I really did enjoy
the cultural differences between my own lab at Stanford and the biotechnology industry.
Hughes: Please talk about that.
Scheller: Well, you had not only to think about whether the experiment would work; you had to think
about was there really a medical need that you were eventually moving towards. What would
the product be? How long would it take to get the experiment done? What outside investors
would think of this area? Those types of issues were never factored into our thinking at all at
Stanford. I found the decision-making process and having to factor in those issues curious and,
because of their novelty, interesting. But the science that people were trying to do, to be
honest with you, was really not particularly fascinating to me; it was superficial compared to
the things that most people were working on at Stanford.
Hughes: Partially because of having to draw research towards application?
Scheller: Yes, having to make it an applied project. In general the scientists were good scientists, but
they weren t given the opportunity to think as freely and as deeply. Their goals were set very
clearly, and they were in a way asked not to think outside the box [but rather] to move towards
those goals at any cost and not to get distracted. Whereas at Stanford we liked getting
distracted by things that were interesting, and it didn t matter whether they had anything to do
with the potential project or not.
Limitations on Outside Activities Imposed by the Hughes Institute
Hughes: Did you ever have any interest or involvement in the social and ethical issues that have been
raised for decades over the possible impact of commercial interests on the way academic
science is conducted and the way academic institutions behave?
Scheller: Fairly little. The Howard Hughes Medical Institute was extremely restrictive and rigorous in
that respect, and we were quite carefully monitored in terms of our consulting arrangements.
We were very carefully monitored in terms of our licensing agreements, our ability to
30
distribute reagents, and so on. The institute is tax-free, public. The endowment is held in the
public trust. They have to be very careful. I was a direct employee of the Howard Hughes
Medical Institute. They had to be very careful to make sure they were squeaky clean in that
respect, particularly given their somewhat shady past.
Hughes: How did they look upon your consulting?
Scheller: They had a maximum amount of stock that you were allowed to have; they had a maximum
fee per day that you were allowed to charge, and so on. It was quite, I thought, unfairly
restrictive.
Hughes: And time restrictions as well?
Scheller: Stanford was one day per week, and the Hughes, I think, was twenty-eight days per year,
something like that. It was again quite carefully monitored. The Hughes, being more
restrictive than Stanford, was quite unfair, and in a way put the Hughes investigators at a
personal financial disadvantage compared to other scientists that had more freedom to consult.
I thought that the Hughes shouldn t worry about how many hours you spend doing things and
that they should judge you on your science; you re either good enough to be a Hughes
investigator or you re not. If you don t come into work at all, and you somehow got the job
done, more power to you. [laugher] Overall, the Hughes was very good to me, and
supportive, so these were minor things.
31
HI DIRECTOR OF SCIENTIFIC RESEARCH, GENENTECH, JANUARY 2001-PRESENT
Decision to Join Genentech
Need for a Change
Hughes: That then begs the question, why did you come to Genentech?
Scheller: There are a lot of reasons. I think that the main reason, and I would say 99 percent of the reason, is
that I just wanted a change in my life. I wanted to do something different. I wanted new challenges.
The academic life is absolutely terrific. I could have very comfortably spent another twenty years at
Stanford being a researcher and been extremely happy. I think that needs to be made clear-you ll
see why.
The main thing was just for a change and for new challenges. It had become easy to be a
professor at Stanford. I got good students; we did good experiments; we wrote papers. Sure I could
have been doing better, I suppose. I could have made more important discoveries, but I was doing
fine. It just wasn t as much of a challenge as it was when I was getting started. I wanted new and
different challenges.
Criticism of the System of Scientific Publication
Scheller: Having said that, I was also fed up with the system of publishers. What you do to publish a
scientific paper is to work for weeks, months, years, to collect the data, to analyze it, to understand
it. Then you send it into a journal. Editors of the journal then judge whether your work is important
enough, novel enough, to be considered for review. The editors, of course, know much less about
the field than you do. They re really not in any kind of a position to make these decisions, but they
make them anyway. Then the papers are sent out to your "colleagues," and I think most people try
to produce fair and rigorous reviews. It s become standard in the field for people to feel as though
they need to be extremely critical of papers, both technically and whether something is
"interesting" enough to warrant being published in journal X versus journal Y. The paper is often
rejected, or it needs much more work, or it needs this or it needs that in the opinion of someone
else. Some of the feedback was very useful; often most of it was either not useful or not realistic.
So you get into a battle with the editor and a battle with the reviewers, and this would go round and
round.
You know what? I got sick of it. I just didn t need it. I just wasn t interested in that anymore. I
think it s a sad thing because as you know from the interview that we ve done all I ever wanted to
be was a scientist, and I feel as though the system took the fun out of it for me. The system doesn t
owe me anything, but I m a little bitter about the system. It s as though it took my childhood dream
32
It wasn t even so much me. I was successful. I was a professor. I couldn t be fired. I was
doing fine. But to try to explain to a student who had worked for years, who wrote what in our
opinion was often a very nice paper why their work wasn t going to be accepted or published-
I didn t think there were really any good reasons. You had to look this kid in the eye and
explain to him. It was extremely painful to me, to where I got to the point where I m not sure
that in good conscience I would recommend to students that they should become academic
scientists.
Hughes: That s sad.
Scheller: I thought, what am I doing here? I agree with you that it s sad. It s gotten so competitive; it s
gotten so political. Academic scientists are often very motivated by prizes~the Nobel Prize,
this prize, that prize. Publishing is the way to move up the ladder towards those prizes, and it
got to the point for me where I just didn t want anything to do with it anymore. That s too
strong a statement. I still publish papers. It s not that I didn t want anything to do with it. I
wanted other things in my life that were as or more important so that I had other things to
think aboutother diversions, other interests, so that it wasn t so deeply important for me to
have my scientific discoveries published in this journal or that journal.
It s even worse than that. So you send the paper in; they often send it back rejected. You
work for the journals for free as a reviewer. They send you papers. You work many hours
studying them and writing critiques. You don t get anything for that so you re working as a
slave for free. You pay to publish the paper you pay page charges. If you have a lot of color
figures sometimes it s thousands of dollars, [voice crescendoing] And then you pay them to
subscribe to the journal! [laughter] They walk all over you: you work for free; you pay to
publish; and then you buy the journal back. What kind of a system is that? Man, they have got
it made, I ll tell you. Anyway, that also was part of [my decision to join Genentech].
I also felt that the scientific conferences were such a big part of science. I enjoyed
traveling all over the world and meeting with people. But I found that when I accepted the job
at Genentech, I canceled sixteen meetings that were all going to be fun and interesting, but I
wasn t really going to learn that much at these meetings. Maybe I could do more good using
my talents somewhere else, other than meeting with my colleagues and discussing the last
couple of weeks worth of data where things really hadn t changed that much.
Seeing Opportunities at Genentech
Hughes: What did the Genentech position offer as a counter to these problems?
Scheller: Again, I want to stress that it was 99 percent just wanting a change. I was not unhappy at
Stanford, as I said. I wouldn t have taken just any job. I think there probably wasn t any other
job, in the Bay Area at least, that would have been exciting enough that I would have left
Stanford. This was a real opportunity. Look, Genentech is a great company, and it s a great
place to work. I have to admit, it s very different coming from a lab where you have twenty
students and postdocs to being head of research where you have 520 that you now supervise,
33
or a building where you can now hire 400 more people, or you re on an executive committee
that runs a billion-dollar corporation. In a way I feel it s a little bit like other phases of your
scientific career; you move on to the next phase where you re doing a number of things that
you were absolutely never in any way trained to do. [laughs] But you either manage
somehow or you re not very good at the job, and you don t manage.
Hughes: Presumably you were thinking about all this before you accepted the position.
Scheller: Well, sure. I knew that I would be interacting mostly with scientists, and I think that I have an
appreciation of what scientists are like, how to talk to scientists, what s important to scientists,
and so on. I thought that I could be a good scientific manager on a larger scale.
Establishing Goals with Arthur Levinson
Hughes: What about doing the kind of science that you were describing when we first started this
conversation today-a more circumscribed, applied kind of science?
Scheller: That s right. We have very specific goals, and that s one of the things that I discussed my first
week here with my boss, the CEO of the company, [Art Levinson]. He gave me written goals,
and I looked at them, and I never had anybody write goals for me before. I discussed with him
how much I really could affect whether I accomplished these goals or not and what it really
meant to have goals. My attitude really was, look, I m going to work hard, and after that it s
sort of up to fate whether I accomplish these goals or not. He in a sort of general philosophical
sense agreed but thought that it was extremely important to be clear what he was expecting
from me. To write it down so that we each had a copy brought that clarity to what he was
expecting. So I have my goals, and I m working on them, [laughter] Let s put it that way.
Hughes: How is it after decades of pretty much being your own master having somebody to whom you
have to report?
Scheller: Well, I do have to report. I also have a lot of freedom and a lot of latitude at Genentech. I m in
charge of research, and I essentially make the decisions about the directions that we re
heading in research. The fact is I like my boss. He was the head of [Genentech] research years
ago, and we get along extremely well, so it doesn t really feel like a constraining relationship
in any way. It feels more that we re working together towards common goals than that he tells
me what to do and I go do it.
Hughes: Does it also make a difference that Art s origins are academic?
Scheller: It makes a big difference that his origins are not only academic but mostly scientific. So if
there s an issue, I can explain the facts to him, and we can analyze it using a shared set of
analytical principles that are the scientific method that we share because of our backgrounds. I
think that helps tremendously.
34
Hughes: Yet as CEO his role is predominately that of a businessman, while yours is as director of
science.
Scheller: Yes, although it really is all related. Some people at Genentech think about how much money
we make. Another way to think about it is how many patients we help. They really go hand in
hand.
m
Scheller: You can think of it in terms of patients, not dollars, and if we help a lot of patients we will
make a lot of money. The way to help a lot of patients is to do good research, to be good
medical scientists, and to discover important therapeutics. Maybe I m still idealistic since I ve
only been here six months, but the fact is our country is set up in a way such that the fruits of
basic scientific research are brought to benefit mankind through private industry. It seems to
be as good a system as any that I ve seen in the history of the world, and that s the way it
works.
Hughes: So putting the patient into the equation was a draw for you?
Scheller: [hesitantly] Yes, it was a draw for me, but I didn t see that I was trying to do anything
particularly profound in terms of changing the world. As a professor at Stanford I was more or
less just trying to stay busy and lead a good life. It s really the same. Sure, it s nice to think
that we re going to help patients, but at the same time I don t- [pause] I don t really think of
it daily in terms of that deep motivation. It s more just getting up in the morning and doing
something interesting to keep myself entertained and of course to lead a good life. But I don t
wake up thinking, "I m merely awake now to go help people." I m just here to do good
science-again, science with a different set of decision-making parameters than when I ran my
lab at Stanford.
Research to Produce Products
Hughes: Talk about how those parameters are different.
Scheller: Those parameters involve working on projects many of which have the potential to lead to
treating unmet medical needs, rather than just anything that happens to be interesting, or any
direction that you happen to go. What we re trying to do here is much harder than what I was
trying to do at Stanford, and that s what a lot of people find hard to believe. They think, gees,
professor at Stanford, that s a hard thing. The difference is really what I ve mentioned already:
At Stanford just so I discovered something kind of cool; it didn t really matter what it was.
Here you can discover something kind of cool and that s valued, but you re really much more
rewarded for discovering something that leads to a medical breakthrough. It can t be just any
interesting thing that happens. And that s what makes it harder. And that s what makes it often
necessary to stay more focused on a particular path and not to go off on tangents that could
just be interesting but wouldn t really lead you to the medical breakthrough. It s as if we have
to discover something specific rather than discovering just anything, and that makes it harder.
35
Hughes: Has it yet happened that you ve been on to something scientifically interesting that didn t have
a clear application and you had to cut it off?
Scheller: [hesitantly] Well, sure. At Genentech there s enough latitude that if it s interesting
scientifically we ll usually pursue it at some level, and that s one of the reasons that I would
have only moved here versus other places. Some of the small companies, their company is on
the line-we re talking the difference between having a company next year or not. There often
isn t the latitude just to do some interesting science. While I try and keep things focused here,
I also encourage all of the scientists to have applied and a more basic research project. The
hope is that some low percentage of the basic research projects will result in technologies for
the future that end up being valuable for the company in a way that we can t easily predict
today.
Dealing with Genentech s Culture
Scheller: I walked into a situation where there was a culture that had evolved over twenty-five years.
Many of the scientists felt entitled to that culture. They felt entitled for the culture to go on the
way it s been for the last number of years that they ve been here, and they didn t want any
change.
Hughes: How would you define this culture that they wanted to retain?
Scheller: I don t really want to get very specific about it, other than to say the way they do things and
what they expect the company to be: The way they expect to make decisions, the way they
expect to be treated, the way they expect the decision process to be made, the size that their
office should be, the pay that they should have, the scientific directions that we should be
moving in-just a whole long list of things that have become ingrained in the culture here that
didn t necessarily fit my vision for what the culture should be. There are 520 employees and
one of me. [laughter] But I get to make the decisions.
Hughes: So how are you doing?
Scheller: So how am I doing? Well, I m still here, [laughter] A number of people have been extremely
helpful. [Genentech] human resource people have helped me with some of these issues.
I ll give you an example: Desks and where they should be situated. At Stanford all the-
desks are in the lab. Every place I ve ever worked the desks are in the lab next to the [lab]
bench. Here, postdocs and RA s and senior RA s-an RA is a research associate-have offices.
We re building a new building. We broke ground on the building, and I looked at it and I said,
"The offices are over here and the benches are there. I want the desks next to the benches."
People had a fit. They felt as though something that they were entitled to was being taken
away from them. They felt that it was being done so that I could watch people more carefully
that I didn t think were working hard enough. They thought that it was being done because
maybe then the senior RA s that were paid a lot would quit, and I could hire junior people and
save money. The fact is, I just don t think that way. I put the desks next to the bench because
36
if you re doing experiments you should want to have your desk next to your bench where
you re working so you can go back and forth and it would be easier.
So this led to my first and one of my most dramatic sets of conflicts of culture with people
here. We reached what I suppose can be called a compromise. As I said, I had a lot of help
from the human resource people at Genentech in organizing town hall-like meetings or
working groups to discuss how this would be potentially organized.
Hughes: Where are the desks going to be?
Scheller. They re in the lab, but they re now called "attached offices," and there s a sliding glass door
in between the desk and the bench, which is a perfectly reasonable compromise.
Fostering Scientific Interaction
Hughes: Well you know, historically you re on the right track. Dave Goeddel told me it was Swanson s
preference to have scientists working in close proximity to force interaction.
Scheller: Absolutely. Now we re so big and we re so spread out that there are people here that don t
know other people; there are people here that never run into each other. I ve tried to foster
greater interactions between the different departments. Now people at Genentech can have
joint appointments in more than one department in order to foster that interaction, something
that s commonly done in academia but had never been done here.
Hughes: How are people taking to that policy?
Scheller: Oh, they think it s absolutely terrific.
Hughes: Do they spend time doing research in different areas?
Scheller: They ve usually been collaborating at some level before. This is a way of formalizing it so
they now come to the seminars and the luncheons and things like that. They remain in the
same physical space but they have a tighter connection to departments other than their own as
a way of formalizing the fact that they re working together, not within a department but often
between departments.
Hughes: Is Genentech like other bioscience companies in having a division of activities?
Scheller: Yes and no. A lot of biotech companies have labs more like Genentech s. But, a lot of the
newer facilities that are being made are going back towards the academic models as a way of
instilling the idea that in part the reason we re here is to be doing experiments, and you
shouldn t want to have your desk anywhere other than next to your lab bench, because that s
where you should be.
37
Scientists at Genentech and Stanford
Hughes: Please compare the quality of scientific discussion and communication at Genentech with
what you were used to in academia.
Scheller: In academia and in industry there s a huge range of scientists, some of whom are the best in
the world and others of whom are not as good. I find that here at Genentech, and that was also
the case at Stanford. The quality of the science here is excellent. The level of discussion is just
as deep. I think there are probably on the average more creative scientists at Stanford than at
Genentech. I don t think there are more at the level of creativity of the best people here. The
best people here are really the same as the best people at Stanford. They re terrific people
both places.
Scheller s Recruitment
Hughes: Tell me about the recruitment process. What were you told you would be doing, and how did
that jibe with actuality?
Scheller: Well, on my first visit I met with Art Levinson, the CEO, and with Dennis Henner. Dennis, in
particular, described the organization of research and the goals of putting molecules into
development to become products. Art Levinson talked more generally about the philosophy of
the companyhelping with unmet medical needs and so on. I think all of those very general
issues jibed very closely with what I was told. Nobody could prepare me for the more detailed
issues, but the general expectations of what I would be doing and what I was expected to do
were very fairly portrayed by Art and Dennis.
Hughes: What did they see in you? Why did they want you?
Scheller: I think they wanted first and foremost a good scientist, and a scientist that the other scientists
would respect. That was very important. You needed to have a scientist of a certain level of
accomplishment that could come into the group, otherwise you d have a lot of people
wondering, why is he the boss? Maybe even so you d have a lot of people wondering that and
wondering, why aren t I the boss? So those 250 papers and a membership in the National
Academy and so on were very important credentials that Art Levinson could hold up in front
of the group of scientists here and say, "Look, this is a good scientist. This is someone that
knows how to do science, and that s why I m hiring the person, and that s why you should
respect him." Your publication record s almost the universal language within science. Other
scientists can look at your CV and see what you have accomplished and then judge for
themselves whether your career has been good, bad, indifferent, outstanding.
Hughes: Did the discipline in which you had achieved, neurobiology, have any significance?
Scheller: That was probably a negative if anything since Genentech really doesn t work in
neuroscience. The techniques that are used by scientists nowadays and the basic ideas of
38
molecular biology and cell biology are so similar among different disciplines that the logic,
the thought processes, are shared among all disciplines. It didn t help me to be a
neurobiologist, but apparently it didn t hurt too much since I m here.
Hughes: Genentech came to you rather than the other way around?
Scheller: Genentech would never advertise a position like this, and even if they did I would never apply.
So yes, they came to me.
Hughes: Had Genentech gotten word that you were restless?
Scheller: Sure, they had heard from their scientific board, probably through David Botstein at Stanford,
that I would consider other opportunities. Then Art Levinson checked with other people, like
Richard Axel who s on the board who I worked with as a postdoc; and with other scientists as
well. I know everybody that s on the Genentech board, so it was interesting that Art really
could have called anybody, and they would have known me at different levels.
Hughes: It sounds, the way you tell it, that your status in science was important to Genentech more for
internal reasons than for external. Did they want to advertise you to the external world as an
accomplished scientist?
Scheller: They certainly did advertise [my appointment] to the external world. I think that was very
important as well. They would have been embarrassed to put up the name of somebody that
hadn t a long list of accomplishments that they could list after his or her name. That was
certainly expected and that was certainly touted in the press releases and so on. That made
Genentech feel proud and accomplished that this was the kind of person they were hiring. So
I think that my appointment was very important for both internal and external purposes.
Although it certainly didn t make such a difference that hiring someone to run research
instantly affected the value of the company in any way. I think no matter who it had been, the
response of the business community is, okay, fine, now let s see what the person can actually
do. I m not going to increase the value of your stock because you hired some guy from
Stanford. Let s see the medicines that come from this guy; then I ll pay more for the stock.
Dennis Henner and David Martin. Previous Directors of Research
Hughes: Was there a passing of the wand from Dennis Henner in terms of philosophy or culture? Does
the director of research position have its own traditions and standards?
Scheller: I think there s quite a bit of difference between Dennis Henner and myself. Dennis had
worked here for twenty years. Dennis never had an academic career. He came here, I think,
after a postdoc, and his whole professional career was at Genentech. It s fair to say that most
people would consider Dennis a good scientist but not a very accomplished scientist. There
were other scientists, like Dave Goeddel for example, who would have been considered very,
very accomplished scientists, all from work they d done at Genentech. We also brought a
different philosophy to how we do science, how we think about scientists.
39
Hughes: Dave Martin came to Genentech directly from academia, just as you did, to become director of
research. How could he help but carry the academic culture with him?
Scheller: Sure. Also with Dave it was a very different company then. That was fifteen years ago or
more. Genentech was much smaller; it was much more of a free-for-all; it was much less
organized and much less focused on a few different areas and so on.
By the way, I don t think that my culture is better than Dennis Henner s; it s just
different. We ll see whether one or the other is more effective, or whether they were both
effective but just in different ways.
Hughes: How do you think that Levinson s goals are going to interact with the academic cultures that
you bring with you?
m
Scheller: Genentech s goals will be best achieved by doing very creative science.
Genentech s Openness about Science
Hughes: What was a surprise to you?
Scheller: [pause] I ve learned a lot about business from the executive committee meetings. The
[executive committee is composed of] six people that fund the company, the CFO [chief
financial officer], the head of legal, the head of operations and sales, the chief medical officer,
and Levinson. I ve learned a lot about the legal system.
There have been two things that were really surprising to me about the science. We are
more open here about what we re working on than in academia, which is exactly the opposite
of what I thought it would be.
Hughes: You mean open to the outside world?
Scheller: About the projects that we have going on, the progress we re making on the projects. If I was
doing something at Stanford, I wouldn t tell anybody until I was really secure that this work
had found a home in a journal or it was going to come out where I was going to get credit for
it. I don t know why that is here, and I still disagree some with that philosophy of Genentech. I
think that we should be less open. I don t see any reason to tell the world what we re working
on. I don t see any reason to tell our competitors, in particular, what we re working on, how
far along we are, what kind of data we re getting. It seems to me to put us at a disadvantage by
telling everyone, yet it seems to be the culture here. I m not sure if that s because we re a
publically held company and we owe it to our stockholders to inform them about what we re
doing. I personally think that it would be in the best interest of the stockholders if we said less
about what we are doing.
40
Intellectual Property in Biotechnology
*
Gene Patenting
Hughes: What about the role of intellectual property protection? If Genentech patents its discoveries,
then one could argue that you don t have to worry about talking about them.
Scheller: That s the other thing that has surprised me. The intellectual property situation revolving
around genes, in particular, is so unbelievably complicated. When I came, I preached to the
executive committee that the whole genome was being divided up, that people were picking
genes that were theirs, and that was going to be it for the next twenty years. So we had to
hurry.
While I was preaching that we had to hurry, it was over already. There are so many
patents on so many genes that I think it s very bad for the industry in general. Somebody
might own the composition of matter-that is the protein encoded by the gene. Somebody else
might own the utility around what that gene might be useful for. Somebody else might own the
actual antibody raised against the protein and have shown that the antibody actually does
something. By the time you divide it all up there s nothing left; there s no incentive for a
company to work with these genes. There s so much intellectual property revolving around the
genes that make up the building blocks of animals. It s extremely complicated; it s extremely
frustrating; and I think that it s extremely bad for the industry and for the future of medical
discovery. It also was a surprise and a bit of a shock to me how much intellectual property
there already was around the genome.
Genentech certainly has its share of that. We certainly have been a player there. We have
our chunk of property that we ll defend and trade and barter and use for our own business and
for our own discoveries. But in the end, my god, somebody needs to actually make the drugs
and to be able to profit and benefit from that. The way it s set up now it s not so clear how
that s all going to unfold in the coming decade. Your question really brought me to the second
big surprise that I had about the way things were done here. If you re in academia you just
work with a gene; you publish your paper; you don t care if somebody owns it. You make it
and publish it; who cares who owns it!
Hughes: Issues such as this go back to the very beginning of commercial biotechnology. There was a
furor over the Cohen-Boyer patent application, for example, the first major patent in
biotechnology. What s happened recently is that the tremendous activity around the human
genome has made the problem more complex and more visible.
Scheller: That s what I m saying. You need to have patent protection in order to protect your company s
investment in the project, in the science, in order to recover a profit, hopefully, from the
medicine that you make, and to recover all of the tremendous research and development
expenses that went into discovering and developing the medicine. But that s been taken to an
extreme where people do projects to capture intellectual property and just stack it up and then
say, "If you want to make a medicine you have to go through me." You don t just make the
medicine and then say, "All right, now I ve done it; it s good for mankind. Now protect me so
41
I can recover my investment and be a good company." You just stack up intellectual property
and prevent people from doing things, trading with people: Have somebody discover, have
somebody make a medicine, and then come around the back and say, "By the way, I own that.
I know I didn t put much work into it, but look at this piece of paper I have; a chunk of it is
mine." That s good business but it s not good for mankind, in my opinion.
Hughes: And it ultimately isn t good for business if each company has only a tiny piece of the pie.
Scheller: And it s all split up in complicated ways, and the legal fees continue to increase and then sky
rocket, and everybody s suing everybody else and round it goes.
Hughes: What s the solution?
Scheller: You just move forward and do the best you can. I think that one of the things that will happen
is that medicines will be more and more expensive. That s a given outcome of all of this. I
think there will be cases where certain medicines aren t made that could have been made that
would have helped people. There will be a proliferation of the legal issues in the industry.
We ll move forward and do the best we can.
Hughes: Why can t there be correctives in the patent system itself?
Scheller: I think there have been to a certain extent. I don t think people are issuing patents on DNA
sequences alone anymore, so there are attempts to correct the system as we move forward. But
what you do then is have the DNA sequence and find out its expression pattern in a disease
versus a normal tissue and propose the utility based on that. So the system corrects itself, and
then science adds a little bit more to allow a patent, and then that may correct itself again; then
we ll add just a little bit more to that. So you can always find ways to seemingly stay one step
ahead of the correction, [laughing]
Hughes: Do you hold patents?
Scheller: I might hold one or two from my work at Stanford but nothing that s particularly noteworthy,
unlike most of the scientists here.
Hughes: Stanford has the reputation of being quite entrepreneurial in terms of the commercial value of
research done by its faculty. And Columbia is no laggard. Please compare the emphasis on
practical application at Columbia, Stanford, and Genentech.
Scheller: As we ve said already it s night and day. At Stanford and Columbia and Caltech nobody really
cares if there s a practical application. If there is, the patent offices of the universities are
anxious to capitalize on it, but it s not the goal. Here patenting s one of the goals.
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Emphasis on Patenting at Stanford and Genentech
Hughes: American research universities in general have become much more appreciative of patenting
opportunities. Say twenty years ago, Stanford was probably leading the pack. Were you aware
of that culture?
Scheller: Sure, but 99 percent of the discoveries that are made at Stanford the patent office was
uninterested in. You say, "I have a discovery; it s this gene." Stanford would say, "Look, it
will cost us $40,000 to patent something, and is anybody really going to be interested in that?"
They would send out queries to companies and say, "Would you be interested in licensing
this?" If the answers didn t come back "yes," they would not pursue a patent. Whereas here
we re happy to patent 600 genes-many of which people may not want; where we don t know
what they do-with the thought that longer term a discovery will happen that will make this
intellectual property valuable.
I think the other thing about patentingthe kinds of patents that happened to come from
places like Stanford and UCSF (recombinant DNA) or Columbia (gene transfer into cells)
were very fundamental technology-type discoveries of twenty years ago or so that were then
very broadly licensed for a very reasonable fee. Stanford charged a few hundred thousand
dollars to license the Cohen-Boyer patent. This wasn t restrictive in any way, whereas
companies may use patents to completely block another company from doing something. So
patents can be used in a much more aggressive way by industry than by academic institutions.
I think that s understandable. It s in the best interests of the companies today. It s not
necessarily in the best interest of mankind.
Scheller s Programmatic Changes
Hughes: Have you made programmatic changes since you ve been at Genentech?
Scheller: Oh sure. That s another thing: If your project is discontinued and you re separated from the
company, you re not necessarily very pleased with me.
Hughes: I can imagine.
Scheller: I can imagine that too. It s not an easy thing for me to make these changes either, but it s
something that one needs to do based on where you think the important discoveries will come
from, who you think will make the important discoveries, and where you want to put your
resources. So we no longer have an endocrinology department; we no longer have a
cardiovascular department. I have let people go, sometimes people that have worked with the
company for a long time fifteen years. These are painful, sometimes controversial decisions
that one needs to make.
Hughes: Did you come knowing that you would do those things?
43
Scheller: [pause] I thought I would probably do those things but hadn t thought about how stressful
they would be to do until I actually began to do them. It s very different than academia. If I
had a student that wasn t doing very well, I just wouldn t talk to him all that much, and he
would work away for a few years, and he d eventually go away. But I didn t fire anybody.
Hughes: Is that power in your hands at Genentech?
Scheller: Absolutely.
Hughes: There s no approval process of any kind that you have to go through?
Scheller: No. Again, something that s different than academia. To let someone go at the university
would be an incredibly involved process. It would be in many cases impossible, [laughs]
Here, if it s in the best interest of the business, it s something that we do.
Hughes: I meant my question to be broader, not about dismissing individuals but about changing
program emphasis.
Scheller: Absolutely, totally at my discretion. Not that I necessarily made the decisions in a vacuum. I
consulted a large number of people of course. But in the end my decision.
Hughes: What did you consider when you were reviewing the various existing programs?
Scheller: I thought about the science. I thought about whether the science that was being done would
reasonably lead to a medical advance and therefore were studies that we wanted to continue.
To be perfectly honest with you, since it involved separations from the company, I don t want
to get into the details.
Hughes: I don t want you to; I m trying to get at your thought process, the conceptual basis, not the
specifics of each decision.
Scheller: The kinds of things that I consider and the kinds of things that are publically said don t always
100 percent overlap.
Scheller s Postdoctoral Fellows Follow Him to Genentech
Hughes: Are you doing any research on your own?
Scheller: Sure. I brought with me five postdocs and my research associate of twelve years. I have a lab
and we re working away. My hour of sanity every week is my lab meeting where we go over
data. We meet in this room. We wouldn t have fit in this room at Stanford but we fit in this
room here. I m not sure that I will keep a lab of that size. These people had nowhere else to go
and I had of course a commitment to them. I announced in December that I was leaving in
seven weeks. That doesn t give a person a lot of time to change their life. So I was happy to
have a number of them move here, and they re actually very happy to be here. Most of them
44
were wondering whether they would pursue a career in academia or industry. They say that
during one postdoc they got to experience both. And in general I think they d say that doing
the science is very similar here.
Hughes: Did you have to negotiate bringing them?
Scheller: I told people here that my postdocs would move. This ended up being a few more than I
actually hoped would move, but as I said they had nowhere else to go. I assumed that they
would want to stay at Stanford or leave. I was surprised that almost everybody said, "Oh, no,
I d love to move to Genentech." Then I thought, "Oh, well, I didn t know you were all going
to want to move." [laughter] I discouraged a few people from moving.
Hughes: What was the reason? Their respect for you or the fact that they wanted to try working in
industry?
Scheller: They were much more open to doing a postdoc and their research in industry than I thought
they would be. It gave them confidence that it was an okay thing to do if I was doing it.
Prevailing Stigma against Industry Scientists
Hughes: In general, academics used to consider that a scientist choosing to go into industry probably
did so because he/she couldn t cut it in academia.
Scheller: There s still a stigma in academia that that s the case. I think it s a one-way street. Most
people in industry don t think that, but that s understandable. Can t say that about me because
I ve done both.
Hughes: What do your academic colleagues say to you about your transition to industry?
Scheller: I think that some of my younger colleagues probably don t get it, but most of my colleagues
that are more my age or older completely understand that I just wanted to do something
different because they probably all thought the same thing themselves.
Hughes: Were you doing any bench science at Stanford?
Scheller: No.
Hughes: Do you miss it?
Scheller: I stopped bench science so long ago that I can t even remember. If I tried to pipette I would
probably not be able to.
45
Genentech s Pharmaceutical Production Capability
Hughes: Part of Genentech s business, of course, is development and scale up. Do those two aspects
broaden the way you have to plan the science? Or can you say, "That s the responsibility of
other departments; my responsibility is to see that good science is done?"
Scheller: Development is taking the molecule and turning it into a drug. Production is really not
something that I work on or think very much about. I am awestruck by what Genentech does in
terms of manufacturing. The thought that in my lab we grow a little flask of a couple-of-
hundred mils that we shake around and work on, whereas in our production plant we do
12,000-liter fermentations. When we make protein, if we make a milligram it s a lot. Over the
course of a year here we make hundreds of kilograms of pure protein. The scale is something
that I still can t even fathom, and therefore it s just amazing and remarkable that it gets done.
So I respect it immensely and it s science in its own right engineering really, which I consider
science-that requires tremendous technical innovation and creativity, precision, organization,
all leading to something that ends up in a bottle that is sold, shipped, in a doctor s office, and
helps someone. It s incredible that it ever gets that far.
##
Scheller: [The scale-up] is done largely by the process science group. These are not cheap drugs to
make. Then you worry about ways for making cost improvements in the manufacturing. It s
not the case that every batch works out. You work towards improving your yields so that the
fermentations don t get contaminated and you have to throw it all away, or one of the steps
doesn t work for some reason and you have to start over. That can cost many millions of
dollars. But that s something that Genentech is very, very good at because of its long history
of having recombinant products so early on in the history of the industry.
Hughes: The process science people could say, "That s a grand discovery that you ve made, Dr.
Scheller, but if you only did it in this way it would make our lives much easier. Would you
please put it in an aqueous medium," or whatever.
Scheller: Sure. The cost of goods: "If you only did it this way we could actually afford to make it and
sell it to people. Since it s that way it is going to be so expensive that nobody s going to want
to use this." There s fairly little of that done since we make a set of antibodies or proteins.
What we re looking for is a cell line which produces a good amount of the protein. We and
process science can usually come up with that. It s an area of research that we do work on:
"Gee, if we make a gram per liter, if there is some way we could make two grams per liter,
we d get twice as much for the same amount of money. That would be a great thing for the
company in terms of profits." So we do some research into increasing the yields of protein
expression.
46
Genentech s Research Review Committee
Hughes: I read of the Research Review Committee which apparently you chair. Would you say
something about its functions?
Scheller: The research review committee decides on the directions of research for Genentech. So all of
the projects are presented to the standing members of the committee and invited reviewers.
We then discuss the project with the scientists that have presented. We then ask the presenter
to leave, and we have a discussion amongst ourselves, including the invited reviewers. We
then ask the invited reviewers to leave, and then the standing members of the committee draw
up a set of action items of our recommendations on how the project should continue.
I ve asked all of the scientists at Genentech to present a RRC-Research Review
Committee-presentation over the course of the first year that I m here so that I can get to
know both the scientists and the work that they re doing in much more detail. Some scientists
present a lot of RRC s, and other scientists have been here five or more years and never have
presented one. This again is meeting with various levels of enthusiasm. But it s not optional.
The Hoffmann-La Roche Presence at Genentech
Hughes: Is Roche a presence?
Scheller: No. Four times a year for a day and a half. We were supposed to have a meeting last week
which of course we didn t go to [because of 9/1 1]. Once a year in New York, three times in
San Francisco. I present research [to Roche] once a year. It was supposed to be last Thursday,
the first talk that I ve practiced in twenty years, and now I ll never give it because of the
tragedy.
Hughes: I m not asking for the specific content, but is it a status quo report or a projection of what is to
come?
Scheller: A review of where we stand and where we re headed.
Hughes: It s intended for information purposes, not for approval?
Scheller: This particular presentation is for information, feedback on whether the ideas are reasonable
and so on. There are certainly other presentations that we make to the board for approval:
capital expenditures, stock options, acquisitions, and so on, that require their approval.
47
Schelier s Scientific "Instinct"
Hughes: You have been described in some of the press that announced your arrival as "having an
incredible instinct for science." Is there anything more to be said about what goes into that
instinct ?
Scheller: It s not that complicated. It consists of two factors: What I would call your inborn or innate
ability to think about the world around you. There isn t very much you can do about that;
whatever you re bom with is what you get. I presume that I have some at least average talent
there. Then your experience, which is also something that I suppose is in part innate: How
interested you are; how much time you ve spent thinking about science, honing your instincts,
developing your instincts, refining them. Since I always wanted to be a scientist and have been
thinking about science since I was ten years old, I now have thirty-seven years of experience
thinking about science and refining my "instincts." So I think that it s the combination of your
innate ability and your experience that gives you what people call "instinct."
Scheller s Contributions
Hughes: What do you see as your most significant contribution thus far?
Scheller: To Genentech, or to science, to the world?
Hughes: I ll leave it to you to define.
Scheller: Well, I think the scientific discoveries that I ve made are my most significant contributions,
and that the contributions of the last decade-understanding how the membrane compartments
of cells are organized is a very fundamental set of contributions to modem biology that have
changed the way a lot of people think about cells. That s certainly the set of contributions that
I m proudest of-period.
Thoughts on the Oral History Process
Hughes: Anything you would like to add?
Scheller: No, I think this has been an interesting process and an interesting project. I m wondering what
happens to projects like this, and how you feel about it. You ve listened to me and I ve talked.
We re going to transcribe this. It s going to end up somewhere. I m wondering what real value
this is going to have for mankind. Who s ever going to read this? Who s ever going to know
about this? Why do you do this?
48
Hughes: Now I m on the spot. Why I do this interview with you is because the university has agreed
with Genentech to do it. But long before this agreement I was interviewing scientists
associated with the biosciences and biotechnology. The reason that the university is behind a
project like this is to create resources for present and future research use.
Maybe a useful way to think about it would be to imagine what we would learn if we
were able to have this kind of a discussion with Pasteur or Madame Curie, one that went
beyond formal publications, which often are all we have from scientists, particularly
nowadays when people don t keep diaries; they don t write letters; their scientific publications
in many cases are pretty much it. You lose a lot of "why" context-the reasons that a person s
science took the directions it did. You ve been describing the many reasons, beyond the
intellectual, for your science going the way it did. I for one find that very interesting, and I
hope and I think and I know that others do too. Perhaps in a hundred years it will be even more
interesting because the external circumstances will be so very different. Science itself may
not be fundamentally different since science, put simplistically, is trying to discover more
about the world. That presumably will always be its basis. But just think not only the
technological breakthroughs, but maybe even the ends that people have, the reasons that they
do science, may be somewhat different. Who knows? But at least we have documentation of
what a number of people in the early twenty-first century thought were the reasons they were
doing science.
Scheller: Sure, something to compare it to for a hundred years from now. Good.
Hughes: Thank you for your participation.
Further Discussion of Scheller s Graduate Student Years at Caltech
[Interview 3: January 11, 2002] ##
More on the First Cloning of Synthetic DNA
Hughes: At the request of Genentech, we initially omitted discussion of the somatostatin project, which
was your first brush with Genentech, because of current litigation with City of Hope. We have
recently been given clearance by Genentech s legal department to talk about it and the work
on insulin and growth hormone. You weren t involved with the two later projects. So let s
return to your graduate student days, which we discussed in the first session.
Before we discuss the somatostatin project, I want to take up a point that Stephen Hall
made about Wally Gilbert s visit sometime in early 1976 to Dickerson s lab at Caltech. 6 Do
you remember this episode?
6 Stephen Hall, Invisible Frontiers: The Race to Synthesize Human Gene. Redmond, WA:
Tempus, 1987, pp. 73-74.
4.9
Scheller: Yes.
Hughes: Apparently he gave you some advice.
Scheller: Sure. Itakura had synthesized the 21 base pair lac operon DNA. We wanted to clone it.
Cloning wasn t very advanced at the time, and the ends of the DNA were blunt ends; they
weren t sticky ends. It was known that you could open up a plasmid with a restriction enzyme.
EcoRl was the first one that was widely used. But the way the restriction enzyme worked left
an overhanging, single-stranded portion of DNA. So the synthetic DNA was not compatible
with the plasmid because it was blunt ended. One needed a way to make it compatible.
We knew that Herb Boyer had an 8 base pair fragment of DNA that corresponded to the
EcoRl restriction enzyme site. So we had the restriction site, and we had the lac operon DNA,
and they all had blunt ends, but there was no known way to get them together. So Gilbert I
don t know how-I can t believe that he actually read it knew that Khorana had published a
paper as part of a massive number of papers on synthesizing genes the old way. He
demonstrated that RNA ligase-not DNA ligase-catalyzed a blunt-ended joining of DNA
fragments or a ligation. So that s where the idea came from to take the 21 base pair of DNA,
to ligate on the 8 base pair EcoRl restriction enzyme sites, to then cut that with EcoRl, and
then the sticky ends of the synthetic DNA would match the sticky ends of the plasmid that
could be ligated together. That s what was done, and that was, in fact, the first cloning of
synthetic DNA. That was the first example of where chemically synthesized DNA actually
functioned in a living cell. Remarkable.
I remember going home that night to a [Passover] seder; it wasn t a religious seder. I
didn t even know what a seder was since I was raised as a Christian. But some friends I lived
with near Caltech used that as an excuse to have a dinner party and to drink a lot. [laughs] I
told everybody that synthetic DNA had been shown to function in a living cell. I could hardly
eat. A lot of these people weren t scientists; I m not sure that it meant very much to them, but
it did to me.
Hughes: And that was 1 976?
Scheller: I d have to check; it s so long ago. When did the Nature paper on cloning the lac operon come
out?
Hughes: I can find it, but I don t know right now. 7
7 H. L. Heyneker et al., "Synthetic lac Operator DNA is Functional In Vivo," Nature 1976,
263:748-752.
50
Somatostatin: Genentech s First Research Project
Deciding on DNA Synthesis
Hughes: How did you come to be involved in the somatostatin project?
Scheller: [pause] The somatostatin experiment started when I was a graduate student and Itakura was at
Caltech, and that really was the only facility in California, maybe in the United States, to
synthesize DNA using the triester method that Itakura invented.
Hughes: People like Khorana and Sarah A. Narang were using the diester?
Scheller: Well, Khorana was using diester. That method was much, much slower, and the yields were
much lower. The chemistry had to be done in water, and water s not a good place to do
chemistry because it s just so reactive. Narang was a student of Khorana s, and he left and
started his own lab. Itakura then joined Narang s lab as a postdoc, and he developed the
triester method when he was working with Narang, and he brought it to Caltech to work on the
lac operon project.
After Herb met Bob and they decided to form Genentech, Herb recognized for a number
of reasons that the easiest way to get a gene was to synthesize it. First of all, that got you
around the NIH guidelines. Remember, one of the abundant sources of insulin and growth
hormone was from tumors. People at the time were worried that if you cloned RNA s and
cDNA s from tumors, you might clone something bad, and that something bad would get out
into the sewers. It turned out not to be the case, but people were worried about that. I think
Herb recognized that you could get around that if you synthesized the gene. There were no
cells, for goodness sakes, so how could you get [infected] by mistake?
Choosing Somatostatin as the Molecule to Clone
Scheller: But the synthesis, even though it was a hundred times faster than Khorana could do it, wasn t
robust enough to synthesize a real big gene; they had to synthesize a little gene. People
thought about what s little but still biologically active. That turns out to be peptide hormones-
things like growth hormone, only much smaller. One that was well characterized, meaning it
had a physiological activity and there was an antibody available that would recognize it, was
somatostatin. [The somatostatin project] was a proof of concept of the whole idea of
producing a human protein in a cell. I m not sure if the idea of the specific hormone came
from Art or from Herb. It might have come from Art Riggs.
Hughes: I m pretty sure it came from Art.
Scheller: Somatostatin was a good one to choose. He could have chosen any number of them.
51
Hughes: As you well know, Swanson wanted to go straight to insulin and had to be persuaded that
somatostatin was the wiser route.
Scheller: Right, and the difficulty there, of course, was that insulin s larger. There were two chains of
insulin that had to come together in order to make the active molecule, not something that
bacteria know how to do.
A Failed Attempt at Caltech
Scheller: There was a step that never worked out, which was that we d put in the first several amino
acids of somatostatin and then probably p-galactosidase behind it. I don t know if anyone ever
talks about this because it didn t work. It s probably my fault that it didn t work.
Hughes: But that was what you were told to do?
Scheller: Itakura and I synthesized two pieces of DNA and encoded the first few amino acids of
somatostatin. We were then going to put |3-galactosidase in frame so that we d make the first
few amino acids of somatostatin, then p-galactosidase. We felt that that was enough to show
that we could direct the bacteria to make what we wanted. Itakura and I made pieces of DNA
at Caltech. I think the one that I was synthesizing was probably particularly tricky, and I
wasn t as good at it as Itakura. It had a lot of G [guanosine] and C [cytosine] in it, and the
piece I tried to make didn t work out.
Hughes: G s and C s are harder to synthesize?
Scheller: G s in particular. So the piece I was making didn t work out.
Hughes: You mean it had mistakes?
Scheller: Well, it wasn t right for some reason. So, yes. Whether it had mistakes, or it just didn t have
something it was supposed to have; or it had something that it shouldn t have, I don t
remember.
It was at that time that Itakura was moving to the City of Hope. His labs were done there.
He was recruiting in more and more people, so it wasn t just the two of us anymore. It was
easier for him to more rapidly synthesize the whole gene, which took several pieces of DNA,
not just two pieces, because he had several other chemists coming in.
Hughes: Which he did at City of Hope?
Scheller: Yes, although he started at Caltech.
Hughes: You mean, started on synthesizing the whole gene?
52
Scheller: He certainly brought things from Caltech that he used at the City of Hope. How far he got I
don t remember.
Hughes: Did you drop out at that point?
Scheller: Yes.
Scheller s Confidence in Bacterial Production of Human Peptides
Scheller: So then I decided, "Of course this will work. All I have to do is put the DNA in there. Of
course the bacterium doesn t know what to do [without the DNA code]. It s going to make
whatever protein [coded by the DNA] you put in there." That s a no-brainer.
Hughes: Well, I don t know that it was a no-brainer to everybody.
Scheller: Oh sure. How could it not work?! If the whole foundation of molecular biology was wrong it
wouldn t work. But that was pretty unlikely.
Hughes: At that point enough was known about E. coli as compared to a eukaryotic cell that you
wouldn t expect it to reject eukaryotic DNA?
Scheller: There was more known about E. coli.
Hughes: Well, I know that.
Scheller: An ammo acid s an amino acid, and you knew the genetic code. So what could have gone
wrong is that the RNA might not have been stable enough; the E. coli might have degraded it.
Or the protein that was made might not have been stable enough.
Hughes: Or didn t fold right.
Scheller: But it s a peptide; there is no folding of the peptide. It doesn t have a [three-dimensional]
structure. That s also why somatostatin was a good one to try in the first place.
Hughes: Was that actually thought about? Somatostatin doesn t have a three-dimensional structure;
this is another reason why we should have somatostatin as our test molecule?
Scheller: I don t remember that ever being discussed. It was mostly just that somatostatin was small.
And remember, it was made as a fusion to p-galactosidase, so it was made as part of a bigger
protein. Then it was cleaved away from the P-galactosidase by treating with cyanogen
bromide, which will cut the protein chain at the position of a methionine. That was done in
vitro that was done outside it when there was no more E. coli left.
53
Initial Failure
Hughes: Was another consideration that there was a methionine?
Scheller: It was a worry that the protein might not be detected, even though it was made, because it was
degraded.
Hughes: That did happen.
Scheller: I don t remember.
Hughes: Well, it happened after you dropped out of the project. Swanson had flown down to City of
Hope at a stage where the E. coli were supposed to be spitting out somatostatin, and nothing
came out. Swanson practically had a heart attack. It was later found later that E. coli was
chewing up the somatostatin, which was only being produced in a very small amount.
Scheller: Right, but that was why the antibody was originally thought to be useful and that even if the E.
coli didn t make a lot of somatostatin, even if the E. coli made a tiny, tiny amount, that their
antibody detection was so sensitive that it would be detected that way. So not like the
kilograms that we make nowadays. If billions-fold less was made, you d still be able to detect
it. That would be evidence that even though the process wasn t effective, that at least it was
working. The details and the ins and outs of exactly how all that happened and whether it
worked exactly the first time, I don t know because I wasn t there.
Hughes: It didn t work the first time. I thought it was at that point that they decided to make a fusion
protein which E. coli would be less likely to chew up.
Scheller: It might have gone through [three] phases. The first one we were going to make was definitely
a fusion protein. Then maybeI don t remember exactly it was decided to make just
somatostatin. Then maybe that didn t work, and it was decided to make a fusion protein again.
Hughes: I know it was a fusion protein that was in the end successful.
Scheller: That might have been it: fusion protein-straight somatostatin didn t work; partial somatostatin-
fusion protein didn t work because of a bad piece of DNA; full-length somatostatin, not fusion
protein, didn t work because the protein was degraded; then full-length somatostatin-fusion
protein did work.
Caltech had an agreement with Genentech and royalties were worked out. I don t have
any records of that. Tom Kiley came to Genentech and negotiated with the technology-transfer
people at Genentech royalties and this, that, and the other thing.
54
Somatostatin Research to Bolster a Patent
Hughes: Is that enough on somatostatin?
Scheller: Only that it went on and on and on. Somatostatin s still going on. There are still courtroom
challenges of the Riggs-Itakura patent. Ten years later Riggs was still doing experiments to
isolate somatostatin in a way that was more to support the patent position than to extend the
life of the patent. For god s sakes, the science had moved so far beyond that in ten years.
There was no scientific reason to isolate somatostatin and show it was pure; it was never
going to be a product. Insulin was for sale, on the market; growth hormone was for sale. Why
do it with somatostatin? After the initial demonstration, the work moved on for years without
any true intellectual contribution. It was only strengthening patent positions.
Hughes: As you know, Riggs-Itakura is a very broad patent. I ve heard it described as the corporate
counterpart of the Cohen-Boyer patent. So it has implications, I would suggest, that are far
broader than its application to somatostatin.
Scheller: Sure, although in the end the money that was made for Genentech and the City of Hope was
very significant back then. Compared to [income from] a single product, it s a small amount
of money. I never thought I d be saying hundreds of millions of dollars is a small amount of
money. That s the kind of job I have now.
Hughes:
Scheller:
Hughes:
Scheller:
Hughes:
Scheller:
Hughes:
Scheller:
Stock Options for a Graduate Student
You got the stock that put you on the front page of the Los Angeles Times after Genentech s
IPO [initial public offering].
I got the famous stock; yes I did.
Were you surprised by the stock offer? It s not what the average graduate student of that era
would expect.
[pause] Well, yeah, sure, I guess. Although Itakura and Riggs had talked about stock.
And, of course, they must have gotten some.
Some?! They had a huge amount, or what turned into a huge amount.
So stock was in the wind.
I just took the piece of paper and put it in a drawer somewhere and didn t really think very
much about it.
55
Hughes: You didn t think about it because you suspected the company might not make it? Or did you
think, stock is something unfamiliar to me. It is not what most academic scientists of this era
are exposed to. They re not usually offered stock for working on an experiment
Scheller s Confidence in Genentech s Success
Scheller: I had a ponytail halfway down my back. I smoked marijuana every day. I didn t give a damn
about money or stock or anything. I was a scientist. I didn t, fortunately, throw it away, but it
didn t really mean anything to me. I always thought the company would be successful.
Hughes: Oh, you did?
Scheller: Oh sure.
Hughes: Why?
Scheller: Because it just made sense scientifically. It had to work, I was sure there would be ups and
downs. But it had to work. Otherwise, as I said, the whole foundation of molecular biology
was wrong. It had to work. I didn t want to do something that had to work. I didn t want to be
an engineer. I wanted to discover new things that no one else knew and understand how
animal cells work. It clearly was exciting to other people, but if you re a basic scientist that
wants to understand the mysteries of nature, making a protein in bacteria is like being an
engineer. It s like building a building with a set of instructions rather than discovering what
matter is like that the building is built on. So that was my motivation for leaving the project. I
wasn t discouraged by failure or anything. It was actually exactly the opposite I was sure it
would work.
Biology Begins to Become Corporate
Biologists with Corporate Ties
Hughes: You don t talk-probably significantly-of any feeling of impropriety for collaborating with the
corporate world, which, for a biologist of that era, was not nearly as common as it is
nowadays. You were just thinking, I m interested in basic science questions so of course I will
remain in academia?
Scheller: Yes, that s what I always wanted to do. We talked about that months ago. Since I was three
feet tall I wanted to be a scientist not an engineer. I m not sure it s really different, but in my
mind it was different.
56
Hughes: Do you remember any discussions about Genentech and the controversy that it was causing?
One concern was the acceptability of academic biologists making money through a company.
Herb Boyer really got it at precisely that time.
Scheller: Sure. There were discussions about it, but I wasn t that much involved in those kinds of
discussions. I don t know if my graduate-student peers said anything behind my back, but
nobody ever said to me, "This is a bad thesis project. It s not real science." I was well aware
of those discussions, but it was not very long after that that Wally Gilbert started a company
[Biogen], and X and Y and Z. Boyer might have gotten it, but he got it for only a little while
before it was something everybody was doing.
Hughes: One of the sticky points concerned the postdocs who before Genentech had buildings had
laboratory space in Herbert Boyer s own laboratory at UCSF.
Scheller: I knew Heyneker and Paco Bolivar [were getting paid by Genentech].
m
Hughes: You were in a somewhat similar position at Caltech. I don t know if you were getting money,
but you were getting stock.
Scheller: I was getting money. I was getting an extra check from Genentech every month. It s almost
laughable now, but a few hundred dollars. This made me, I would say in quotes, "a rich
graduate student." Instead of making $8,000 a year, I probably made $15,000 a year, and I was
rich, [laughs]
Hughes: Was this common knowledge?
Scheller: I think that my friends probably knew; I m sure I told them. But I don t think it was broadly
known. I m not even sure Caltech knew. I don t remember.
Hughes: It did cause problems in the Boyer lab-between those who had a Genentech stipend and those
who didn t.
Scheller: Boyer s lab was different than Richard Dickerson s lab where Itakura and I were working.
Boyer s lab was a much more active place with lots of students and postdocs. Dickerson s lab
was very small, mostly technicians, more senior technicians, and not a lot of students. So it
was a much quieter, less competitive environment than Boyer s. I can imagine that it would
have caused problems up here.
Jealousy as a Motive for Criticizing Commercialization
Hughes: It was a volatile situation because of the recombinant DNA controversy. UCSF and Stanford
were in the news.
57
Scheller: Sure. I think the chemists and the engineers and some of the physicists were laughing at us.
The chemists had been interacting with companies for decades. These crazy biologists just
needed to calm down and get this worked out. I think that most of the fervor came from
jealousy and that maybe some people even convinced themselves that it was wrong, or not as
moral-I wouldn t call it immoral-to be associated with a company. But I think that it was
mostly jealousy. Because those people that thought it was wrong and less moral I m sure are
associated with companies; so they either changed their minds, or they didn t really
understand their motivation in the first place. I think it s the latter.
Hughes: Times have changed, and the culture now not only doesn t disapprove, but actually encourages
technology transfer. The corporate world is looked to as the place to produce products for
human health, etc.
Scheller: Sure, but that was always the case. UCSF might have been a little naive in that respect
because it s a medical school. Stanford has a chemistry department where the scientists had
been working with Merck and Pfizer and so on for decades, and an engineering school where
all of the faculty consult, and so on. So I think it was the medical scientists, the biochemical
scientists, needing to go through this little period of understanding about how our country
works.
Hughes: Stanford from [Frederick E.] Terman days on has been a very entrepreneurial place. But until
fairly recently, UCSF has been clinically oriented; it hasn t had industrial ties.
Scheller: I don t understand that completely. Certainly, the physicians consulted heavily with drug
companies for more than fifty years and were conducting clinical trials while often being on
the payroll of the drug company. I think you ve said it right: it was the specific culture of the
life scientists that just hadn t been through this before.
I think you don t have the balance quite right. I think there was much more jealousy
behind this than real soul-searching and morality. These experiments were so widely talked
about, Genentech was so widely discussed, it was clear there was a lot of potential for money
involved. It was clearly in the news, on peoples minds. So it might not even have been Boyer
and his money as much as Boyer and all the attention that he was getting: "He s getting all this
attention, but he s not really a scientist. He s just doing it for the money." That s jealousy;
that s nothing to do with morals. Of course it was more complicated, but maybe not as
complicated as you think, [laughter]
Observations on Genentech Culture
Hughes: What were your perceptions of Genentech culture when you first arrived? What kind of
adaptions did you make, coming from academia?
Scheller: Well, some of the culture is different and some is the same. I think a lot of the people could
get up and walk out of their lab here and walk into a lab at Stanford and sit down and not skip
58
a beat. They could do at Stanford exactly what they do here and be the same scientist, the
same person, the same everything..
They have a little more of a 9-to-5 culture here than at Stanford, but I think that reflects
the much larger number of research associates and senior research associates, technicians.
There are more technicians per lab and no graduate students. We don t have people young
enough to stay up all night. We have a lot of postdocs; they re just a little bit older, and they
still stay up all night here and at Stanford. But there aren t as many here, so it s a shift to a
non-graduate student, technician-oriented culture. The average age of a person in the labs
here is probably some years older. There s a different feel. There are no undergraduates here.
Undergraduates are so naive that it s terrific. I love undergraduates. I miss the undergraduate
students and the graduate students, and that s the biggest difference, and that reflects itself in a
lower level of motivation. The culture s different than in some of the smaller companies. In
some of the smaller companies you maybe have to sleep in the lab to get your experiment
done, otherwise you re going to run out of money and you re not going to have a job.
Hughes: That s a motivator.
Scheller: You damn well better believe it! [laughter] If you go home here and you do your experiment
the next day, instead of staying up all night, you re still going to have a job, because
Genentech sells a lot of medicines, so they re not going to run out of money. And that s a
difference between the old days of Genentech and now, when people slept here because they
weren t sure whether Genentech was going to run out of money.
Hughes: Does personality come into it?
Scheller: Oh sure. And competitiveness and all of those kinds of things.
Encouraging Passion for Science
Scheller: I m trying to bring the balance back towards that intense passion for science.
Hughes: How do you do that?
Scheller: Well, by the kind of people that you have here-hiring a lot of new people, making sure that
those people are the kind of intense scientists that you want. Basically, I think, by just
bringing in new people.
Hughes: Why do intense people want to come to Genentech?
Scheller: To do science.
Hughes: But why here? There are many places to do science.
59
Scheller: [pause] Why here? Well, because of the other people, because of the history, because of the
kinds of things we re trying to do. I like to think, in a small part, because of me. Because of
some of the other great people that are here.
Larry Lasky, who was a postdoc at Caltech when I was a graduate student, came to
Genentech. The first week in January was his twentieth year here. He s resigned. I have of
course known him for twenty-five years, whatever. He said to me, "Well, I m going to leave."
I had gotten wind that this might be the case, and I said, "Well, do you want me to try to talk
you out of it?" He said, "Richard, don t try and talk me out of it. I m just doing what you did.
You left Stanford to come here for something new and different, to get more excited again
about life. I m doing the exact same thing you did. So then I said, "Well, then there s nothing
to say. Good luck." He s going to go to a venture capital firm, so he s trading his blue jeans
for a tie. It s those kinds of people that have gone through at Genentech what I went through at
Stanford: they ve been here so long, it doesn t seem as new and different and exciting as it
used to be, just because they ve been doing it for twenty years. People like that are leaving.
I m not sure I mind so much that they re leaving. What we ll do is find someone out of a
postdoc that s all fired up-that fire in their belly that wants to come in and change the world.
Hughes: There s a paradox, to my mind, about what success means to a company. Some of the
attraction to a small company is that you can turn on a dime; it s new; it s exciting. But the
price that often comes with success is more corporate structure, more restrictions, more rules,
larger size, and, as you re saying, people having been there long enough that it begins to get
old.
Scheller: Well, we talk a lot about that in our executive committee the group of six people that run the
company. We talk about what aspects of our culture we can scale to the size that we are now. I
think it s Lou Lavigne, the CFO, who said, "What parts of the company are scalable?" That s
something that s on our minds all the time because we d like to keep it the innovative,
creative, dynamic place that it has always been. But the point you raise is: Is that possible?
It s clearly not possible in every aspect of the company, but it s probably more important to
try to keep that in research than anywhere [else].
Hughes: And that s your responsibility.
Scheller: Sure, no problem, [said facetiously] [laughs]
Hughes: You wanted challenges; you ve got challenges.
Scheller: I ve been here ten months. No problem. Sure, [laughter]
Hughes: Well, you need to get to your beer session. Thank you for your insights.
Transcribed by Jessica Ross Stem
Final Typed by Caroline Bridges
60
61
TAPE GUIDE-Richard Scheller
Interview 1: August 16, 2001
Tape 1 , Side A 1
Tape 1, Side B 8
Tape 2, Side A 15
Tape 2, Side B 22
Interview 2: September 21, 2001
Tape 3, Side A 27
Tape 3, Side B 34
Tape 4, Side A 39
Tape 4, Side B 45
Interview 3: January 11, 2002
Tape 5, Side A 48
Tape 5, Side B 56
Tape 6, Side A 59
Tape 6, Side B not recorded
62
CURRICULUM VITAE
Name:
Born:
Address:
Education:
1971-1975
1975-1980
1980-1981
1981-1982
Current Position
2001-
Richard H. Scheller
October 30, 1953, Milwaukee, Wisconsin
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080
Phone: (650) 225-4952 Fax: (650) 225-4265
University of Wisconsin-Madison
B.S. - Biochemistry with Honors
California Institute of Technology
Ph.D. - Chemistry - Advisor: Eric H. Davidson
California Institute of Technology
Postdoctoral Fellow-Division of Biology
Advisor: Eric H. Davidson
Columbia University-College of Physicians & Surgeons
Postdoctoral Fellow-Molecular Neurobiology
Advisors: Richard Axel and Eric R. Kandel
Senior Vice President - Research
Genentech, Inc.
Academic Appointments:
1 982- 1 987 Assistant Professor, Department of Biological Sciences,
Stanford University
1 987- 1 990 Associate Professor, Department of Biological Sciences,
Stanford University
1 990- 1 993 Associate Professor, Department of Molecular and Cellular
Physiology, Stanford University
Associate Professor (by courtesy), Department of Biological
Sciences, Stanford University
1 990- 1 994 Associate Investigator, Howard Hughes Medical Institute,
Stanford University Medical Center
1993- Professor, Department of Molecular and Cellular Physiology,
Stanford University
Professor (by courtesy), Department of Biological Sciences,
Stanford University
1 994-200 1 Investigator, Howard Hughes Medical Institute, Stanford University
Medical Center
Fellowships, Awards, Honors:
1 976- 1 980 Nffl Predoctoral Fellowship
1981-1982 NIH Postdoctoral Fellowship
1983 McKnight Foundation Scholar
1983 March of Dimes Foundation: Basil O Connor Award
64
Fellowships, Awards, Honors: continued
1 984 Alfred P. Sloan Research Fellow
1 984 Society for Neuroscience Young Investigator Award
1985 Klingenstein Fellow in the Neurosciences
1985 Presidential Young Investigator Award
1986 Pew Scholar in the Biomedical Sciences
1986 Camille and Henry Dreyfus Teacher-Scholar Grant
1989 NSF-Alan T. Waterman Award
1 992 MERIT Award-National Institute of Mental Health
1993 W. Alden Spencer Award, Columbia University
1 997 National Academy of Sciences Award in Molecular Biology
1 998 Fellow, American Academy of Arts and Sciences
2000 Member, National Academy of Sciences
Editorial Boards, Advisory Boards:
1 984- 1 990 Journal of Neuroscience, Editorial Board
1 984 DNA, Editorial Board
1 985-1990 Annual Review of Neuroscience, Editorial Board
1985 Molecular Brain Research, Editorial Board
1986 Cellular and Molecular Neurobiology, Editorial Board
1 989- 1 99 1 Synapse, Editorial Board
1990 Neuron, Editorial Board
1990 Current Opinion in Neurobiology, Editorial Board
1 99 1 - 1 995 Journal of Neuroscience, Molecular Neuroscience Section Editor
1 99 1 Journal of Cell Biology, Monitoring Editor
1 993- 1 996 National Institute of Mental Health, Molecular, Cellular and
Developmental Neurobiology Review Committee
1995 Genes to Cells, Associate Editor
1 995-1 996 Hereditary Disease Foundation, Scientific Advisory Board
1995-1996 Cold Spring Harbor Laboratory, Neurobiology Advisory Board
1995-1999 McKnight Endowment Fund, Senior Review Committee
1 996- 1 998 Society for Neuroscience, Young Investigator Award Selection
Committee
1 996- 1 999 National Advisory Mental Health Council
1999-2001 Cell, Editorial Board
1 999-200 1 Traffic, Editorial Board
1 999-200 1 Molecular Biology of the Cell, Associate Editor
2000 Neuroscience Research, Editorial Board
65
PUBLICATIONS
1. Scheller, R.H., Dickerson, R.E., Boyer, H.W., Riggs, A.D. and Itakura, K. (1977)
Chemical synthesis of restriction enzyme recognition sites useful for cloning.
Science 196:177-180.
2. Scheller, R.H., Thomas, T.L., Lee, A.S., Klein, W.H., Niles, W.D., Britten, RJ. and
Davidson, E.H. (1977) Clones of individual repetitive sequences from sea urchin
constructed with synthetic Eco RI sites. Science 196:197-200.
3. Sprang, S., Scheller, R.H., Rohrer, D. and Sundaralingam, M. (1978)
Conformational analysis of 8-azanucleosides. Crystal and molecular structure of 8-
azatubercidin monohydrate, a nucleoside analogue exhibiting the "high anti"
conformation. J. Amer. Chem. Soc. 100:2867-2872.
4. Klein, W.H., Thomas, T.L., Lai, C, Scheller, R.H., Britten, RJ. and Davidson, E.H.
(1978) Characteristics of individual repetitive sequence families in the sea urchin
genome with cloned repeats. Cell 14:889-900.
5. Constantini, F.D., Scheller, R.H., Britten, RJ. and Davidson, E.H. (1978) Repetitive
sequence transcripts in the mature sea urchin oocyte. Cell 15: 173-187.
6. Scheller, R.H., Constantini, F.D., Kozlowski, M.R., Britten, RJ. and Davidson, E.H.
(1978) Specific representation of cloned repetitive DNA sequences hi sea urchin
RNAs. Cell 15:189-203.
7. Moore, G.P., Scheller, R.H., Davidson, E.H. and Britten, RJ. (1978) Evolutionary
change in the repetition frequency of sea urchin DNA sequences. Cell 15:649-660.
8. Anderson, D.M., Scheller, R.H., Posakony, J.W., McAllister, L.B., Trabert, S.G.,
Beall, C., Britten, RJ. and Davidson, E.H. (1981) Repetitive sequences of the sea
urchin genome. I. Distribution of members of specific repetitive families. J. Molec.
Biol. 145:5-28.
9. Scheller, R.H., Anderson, D.M., Posakony, J.W., McAllister, L.B., Britten, R J. and
Davidson, E.H. (1981) Repetitive sequences in the sea urchin genome. Subfamily
structure and evolutionary conservation. J. Molec.Biol. 149:15-39.
10. Posakony, J.W., Scheller, R.H., Anderson, D.M., Britten, RJ. and Davidson, E.H.
(1981) Repetitive sequences of the sea urchin genome. Nucleotide sequences of
cloned repeat elements. J. Molec. Biol. 149:41-67.
11. Scheller, R.H., McAllister, L.B., Grain, W.R., Durica, D.S., Posakony, J.W.,
Thomas, T.L., Britten, RJ. and Davidson, E.H. (1981) Organization and expression
of multiple actin genes in the sea urchin. Molec. Cellular Biol. 1:609-628.
12. Davidson, E.H., Thomas, T.L., Scheller, R.H. and Britten, RJ. (1982) The sea
urchin actin genes and speculation on the evolutionary significance of small gene
families. In: Genome Evolution. [G.A. Dover and R.B. Flavell, Eds.] Academic
Press, London, pg. 177-191.
66
13. Scheller, R.H., Jackson, J.F., McAllister, L.B., Schwartz, J.H., Kandel, E.R. and
Axel, R. (1982) A family of genes that codes for ELH, a neuropeptide which elicits a
stereotyped pattern of behavior in Aplysia. Cell 28:707-7 1 9.
14. Scheller, R.H., Jackson, J.F., McAllister, L.B., Mayeri, E., Rothrnan, B. and Axel, R.
(1983) A single gene encodes multiple neuropeptides mediating a stereotyped
behavior. Cell 32:7-22.
15. Scheller, R.H. and McAllister, L.B. (1983) Molecular cloning of a multigene family
encoding neuropeptides which govern egg-laying in Aplysia.. In: Molluscan
Neuro-Endocrinology [J. Lever and H.H. Boer, Eds.] Mon. Royal Neth. Academy
of Arts and Sciences, North Holland Publishing Company, Amsterdam, Oxford,
New York, pg. 38-44.
16. Nambu, J.R. and Scheller, R.H. (1983) Molecular cloning and characterization of
neuropeptide genes from identified neurons. In: Molecular Approaches to the
Nervous System [Ron McKay, Ed.] Society of Neuroscience, Bethesda, MD., pg.
110-121.
17. McAllister, L.B., Scheller, R.H., Kandel, E.R. and Axel, R. (1983) In situ
hybridization to study the origin and fate of identified neurons. Science 222:800-
808.
18. Mahon, A.C. and Scheller, R.H. (1983) The molecular basis of a neuroendocrine
fixed action pattern: Egg laying in Aplysia. Cold Spring Harbor Symposia on
Quantitative Biology: Molecular Neurobiology, Cold Spring Harbor Press, Cold
Spring Harbor, New York, XLVJJI:405-412
19. Scheller, R.H., Rothman, B.S. and Mayeri, E. (1983) A single gene encodes multiple
peptide-transmitter candidates involved in a stereotyped behavior. Trends In
Neurosci. 6:340-345.
20. Scheller, R.H., and Axel, R. (1984) How genes control an innate behavior.
Scientific American 250, 3:54-62.
21. Nambu, J.R., Taussig, R., Mahon, A.C. and Scheller, R.H. (1983) Gene isolation
with cDNA probes from identified Aplysia neurons: Neuropeptide modulators of
cardiovascular physiology. Cell 35:47-56.
22. Rothman, B.S., Mayeri, E. and Scheller, R.H. (1985) The bag cell neurons of
Aplysia as a possible peptidergic multi-transmitter system: From genes to behavior.
In: Gene Expression in Brain [C. Zomzely-Neurath and W.A. Walker, Eds.]
Wiley & Sons, N.Y., pg. 235-274.
23. Scheller, R.H. (1985) Gene expression in Aplysia peptidergic neurons. In:
Molecular Bases of Neural Development. [G.M. Edelman, W.E. Gall and W.M.
Cowan, Eds.] Neuroscience Research Foundation, Inc., New York, N.Y., Vol. 21,
pg. 513-529.
24. Taussig, R., Kaldany, R.-R. and Scheller, R.H. (1984) A cDNA clone encoding
neuropeptides isolated from Aplysia neuron Lll. Proc. Natl. Acad. Sci. USA
81:4988-4992.
67
25. Scheller, R.H. and Schaefer, M. (1985) Neuropeptide gene expression and behavior
in Aplysia. In: Model Neural Networks and Behavior [A.I. Selverston, Ed.] Plenum
Publishing Co., New York, 491-512.
26. Kreiner, T., Rothbard, J., Schoolnik, O.K. and Scheller, R.H. (1984) Antibodies to
synthetic peptides defined by cDNA cloning reveal a network of peptidergic
neurons in Aplysia. J. Neurosci. 4, 10:2581-2589.
27. Taussig, R., Picciotto, M.R. and Scheller, R.H. (1984) Two introns define functional
domains of a neuropeptide precursor in Aplysia. In: Molecular Biology of
Development. [Eric H. Davidson and Richard A. Firtel, Eds.] Alan R. Liss, Inc.,
N. Y., Vol. 19, pg. 551-660.
28. Kaldany, R.-R., Nambu, J.R. and Scheller, R.H. (1985) Neuropeptides in identified
Aplysia neurons. In: Ann. Rev. Neurosci. [W.M. Cowan Ed.] Vol. 8, pg. 431-455.
29. Mahon, A.C., Lloyd, P.E., Weiss, K.R., Kupfermann, I., and Scheller, R.H. (1985)
The small cardioactive peptides A and B of Aplysia are derived from a common
precursor molecule. Proc. Natl. Acad. Sci. USA 82:3925-3929.
30. Scheller, R.H., Kaldany, R.-R., Kreiner, T., Mahon, A.C., Nambu, J.R., Schaefer, M.
and Taussig, R. (1984) Neuropeptides: Mediators of behavior in Aplysia. Science
225:1300-1308.
3 1 . Mahon, A.C., Nambu, J.R., Taussig, R., Shyamala, M., Roach, A. and Scheller, R.H.
(1985) Structure and expression of the egg-laying hormone gene family in Aplysia.
J. Neurosci. 5, 7:1872-1880.
32. Lloyd, P.E., Mahon, A.C., Kupfermann, I., Cohen, J.L., Scheller, R.H. and Weiss,
K.R. (1985) Biochemical and immunocytological localization of molluscan small
cardioactive peptides in the nervous system of Aplysia californica. J. Neurosci.
5,7:1851-1861.
33. Taussig, R., Kaldany, R.-R., Rothbard, J.B., Schoolnik, G. and Scheller, R.H. (1985)
Expression of the LI 1 neuropeptide gene in the Aplysia central nervous system. J.
Comp. Neurol. 238 :53-64.
34. Kaldany, R.-R., Campanelli, J.T., Schaefer, M., Shyamala, M. and Scheller, R.H.
(1985) Low molecular weight proteins of Aplysia neurosecretory cells. Peptides 6,
3:445-449.
35. Schaefer, M., Picciotto, M.R., Kreiner, T., Kaldany, R.-R., Taussig, R. and Scheller,
R.H. (1985) Aplysia neurons express a gene encoding multiple FMRFamide
neuropeptides. Cell 4 1:457-467.
36. Kreiner, T., Schaefer, M. and Scheller, R.H. (1986) The Aplysia neuroendocrine
system. In: Frontiers in Neuroendocrinology. [William F. Ganong and Luciano
Martini, Eds.] Raven Press, New York, N.Y., Vol. 9, pg. 1-29.
37. Kaldany, R.-R., Campanelli, J.T., MakJc, G., Evans, C.J. and Scheller, R.H. (1986)
Proteolytic processing of a peptide precursor in Aplysia neuron R14. J. Biol.
Chem. 261, 13:5751-5757.
68
38. Picciotto, M.R., Johnston, R. and Scheller, R.H. (1986) Neuropeptide genes are not
selectively amplified in Aplysia polyploid neurons. In: Neurology and
Neurobiology. Ion Channels in Neural Membranes. [J. Murdoch Richie, Richard
D. Keynes and Liana Bolis, Eds.] Alan R. Liss, Inc., New York, N.Y., Vol. 20, pg.
429-434.
39. Sossin, W., Kreiner, T. and Scheller, R.H. (1986) Aplysia neurosecretory cells:
Multiple populations of dense core vesicles. In: Fast and Slow Chemical Signalling
in the Nervous System. [L.L. Iverson and E. Goodman, Eds.] Oxford University
Press, pg. 260-278.
40. Shyamala, M., Nambu, J.R. and Scheller, R.H. (1986) Expression of the egg-laying
hormone gene family in the head ganglia of Aplysia. Brain Research 371 :49-57.
41. Mahon, A.C. and Scheller, R.H. (1987) Small cardioactive peptides A and B:
Chemical messengers in the Aplysia nervous system. In: Molecular Neurobiology:
Recombinant DNA Approaches. [Stephen Heinemann and James Patrick, Eds.]
Plenum, New York, N.Y., pg. 173-190.
42. Kreiner, T., Sossin, W. and Scheller, R.H. (1986) Localization of Aplysia
neurosecretory peptides to multiple populations of dense core vesicles. J. Cell Bio.
102:769-782.
43. Kirk, M.D. and Scheller, R.H. (1986) Egg-laying hormone of Aplysia induces a
voltage-dependent slow inward current carried by Na + in an identified motoneuron.
Proc. Natl. Acad. Sci. USA 83:3017-3021.
44. Nambu, J.R. and Scheller, R.H. (1986) Egg-laying hormone genes of Aplysia:
Evolution of the ELH gene family. J. Neurosci. 6, 7:2026-2036.
45. Shyamala, M., Fisher, J. and Scheller, R.H. (1986) A neuropeptide precursor
expressed in Aplysia neuron L5. DNA 5, 3:203-208.
46. Taussig, R. and Scheller, R.H. (1986) The Aplysia FMRFamide gene encodes
sequences related to mammalian brain peptides. DNA 5, 6:453-461 .
47. Shyamala, M. and Scheller, R.H. (1987) Aplysia neuropep tides. In: Progress in
Brain Research. [F.J. Seil, E. Herbert and B.M. Carlson, Eds.] Elsevier Press, Vol.
71, pg. 23-33.
48. Sossin, W.S., Kirk, M.D. and Scheller, R.H. (1987) Peptidergic modulation of
neuronal circuitry controlling feeding in Aplysia. J. Neurosci. 7, 3:671-681.
49. Scheller, R.H. and Kirk, M.D. (1987) Neuropeptides in identified Aplysia neurons:
Precursor structure, biosynthesis and physiological actions. Trends In Neurosci.
10, 1:46-52.
50. Newcomb, R. and Scheller, R.H. (1987) Proteolytic processing of the Aplysia egg-
laying hormone and R3-14 neuropeptide precursors. J. Neurosci. 7,3:854-863.
51. Miles, M.F., Cowan, D., DesGroseillers, L. and Scheller, R.H. (1987) Promoter
sequences of neuropeptide genes in Aplysia californica. In: Molecular Approaches
69
to Developmental Biology. [Richard A. Firtel and Eric Davidson, Eds.] Alan R. Liss
Inc., N.Y., Vol. 51, pg. 563-574.
52. Campanelli, J.T. and Scheller, R.H. (1987) Histidine-rich basic peptide: A
cardioactive neuropeptide from Aplysia neurons R3-14. J. Neurophys. 57, 4:1201-
1209.
53. Taussig, R., Nambu, J.R. and Scheller, R.H. (1988) Evolution of peptide hormones:
An Aplysia CRF-like peptide. In: Neurohormones in Invertebrates. Soc. for
Experimental Biology Seminar Series. [M.C. Thorndyke and GJ. Goldsworthy,
Eds.] Cambridge University Press, Vol. 33, pg. 299-309.
54. Kirk, M.D., Taussig, R. and Scheller, R.H. (1988) Egg-laying hormone, serotonin,
and cyclic nucleotide modulation of ionic currents in the identified motoneuron B16
of Aplysia. J. Neurosci. 8, 4:1181-1193.
55. Kreiner, T., Kirk, M.D. and Scheller, R.H. (1987) Cellular and synaptic morphology
of a feeding motor circuit in Aplysia californica. J. Comp. Neurol. 264:31 1-325.
56. DesGroseillers, L., Cowan, D., Miles, M., Sweet, A. and Scheller, R.H. (1987)
Aplysia californica neurons express microinjected neuropeptide genes. Molecular
and Cellular Biology 7, 8:2762-2771.
57. Maroteaux, L., Campanelli, J.T. and Scheller, R.H. (1988) Synuclein: A neuron
specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci.
8,8:2804-2815.
58. Nambu, J.R., Murphy-Erdosh, C., Andrews, P.C., Feistner, GJ. and Scheller, R.H.
(1988) Isolation and characterization of a Drosophila neuropeptide gene. Neuron
1:55-61.
59. Nambu, J.R. and Scheller, R.H. (1988) The evolution of FMRFamide-like
neuropeptide genes. In: Neurosecretion. [Brian T. Pickering, Jonathan B.
Wakerley and Alistair S.S. Summerlee, Eds.] Plenum Press, New York and London,
pg. 11-18.
60. Newcomb, R., Fisher, J. and Scheller, R.H. (1988) Processing of the egg-laying
hormone precursor in the bag cell neurons of Aplysia. J. Biol. Chem. 263,
25:12514-12521.
61. DesGroseillers, L. and Scheller, R.H. (1988) The molecular biology and physiology
of Aplysia neuropeptides. In: Molecular Biology of Brain and Endocrine
Peptidergic Systems. [Michel Chretien and Kenneth W. McKerns Eds.] Plenum
Press, N.Y.,pg. 299-313.
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137. Pevsner, J., Volknandt, W., Wong, B.R. and Scheller, R.H. (1994) Two rat
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140. Wendland, B. and Scheller, R.H. (1994) Secretion in AtT-20 cells stably transfected
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145. Jacobsson, G., Bean, A.J., Scheller, R.H., Gerggren-Juntti, L., Deeney, J.T.,
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150. Giampietro, S., Shone, C.C., Bennett, M., Scheller, R.H. and Montecucco, C. (1995)
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153. Malgaroli, A., Ting, A.E., Wendland, B., Bergamaschi, A., Villa, A., Tsien, R.W. and
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156. Braun, I.E. A. and Scheller, R.H. (1995) Cysteine string protein, a DnaJ family
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162. Peterson, M.R., Hsu, S.-C. and Scheller, R.H. (1996) A mammalian homologue of
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169. Pevsner, J., Hsu, S.-C, Hyde, P.S. and Scheller, R.H. (1996) Mammalian
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175. Hirling, H. and Scheller, R.H. (1996) Phosphorylation of synaptic vesicle proteins:
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180. Bean, A.J., Seifert, R., Chen, Y., Sacks, R. and Scheller, R.H. (1997) Hrs-2 is an
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181. Zhong, P., Chen, Y., Tarn, D., Chung, D., Scheller, R.H. and Miljanich, G.P. (1997)
An alpha-helical minimal binding domain within the H3 domain of syntaxin is
required for SNAP-25 binding. Biochemistry 36, 14:4317-4326.
182. Hay, J.C., Chao, D.S., Kuo, C.S. and Scheller, R.H. (1997) Protein interactions
regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus
in mammalian cells. Cell 89:149-158.
183. Hay, J.C. and Scheller, R.H. (1997) SNAREs and NSF in targeted membrane
fusion. Current Opinion in Cell Biology 9:505-512.
184. Bock, IB., Klumperman, J., Davanger, S. and Scheller, R.H. (1997) Syntaxin 6
functions in trans-Golgi network vesicle trafficking. Mol. Biol. of the Cell 8: 1261-
1271.
185. Bock, J.B. and Scheller, R.H. (1997) Protein transport: A fusion of new ideas.
Nature 387:133-135.
1 86. Bean, A.J. and Scheller, R.H. (1997) Better late than never: A role for rabs late in
exocytosis. Neuron 19:751-754.
187. Kee, Y., Yoo, J-S., Hazuka, C.D., Peterson, K.E., Hsu, S.-C. and Scheller, R.H.
(1997) Subunit structure of the mammalian exocyst complex. Proc. Natl. Acad. Sci.
USA 94: 14438-14443.
188. Lin, R.C. and Scheller, R.H. (1997) Structural organization of the synaptic
exocytosis core complex. Neuron 19:1087-1094.
189. Chiu, D.T., Lillard, S.J., Scheller, R.H., Zare, R.N., Rodriguez-Cruz, S.E., Williams,
E.R., Orwar, O., Sanberg, M., Lundqvist, J.A. (1998) Probing single secretory
vesicles with capillary electrophoresis. Science 279:1 190-1 193.
190. Advani, R.J., Bae, H.-R., Bock, J.B., Chao, D.S., Doung, Y.-C., Prekeris, R., Yoo, J.-
S. and Scheller, R.H. (1998) Seven novel mammalian SNARE proteins localize to
distinct membrane compartments. J. Biol. Chem. 273:10317-10324.
191. Fujita, Y., Shirataki, H., Sakisaka, T., Asakura, T., Ohya, T., Kotani, H., Yokoyama,
S., Nishioka, H., Matsuura, Y., Mizoguchi, A., Scheller, R.H. and Takai, Y. (1998)
Tomosyn: A syntaxin- 1 -binding protein that forms a novel complex in the
neurotransmitter release process. Neuron 20:905-915.
79
1 92. Hsu, S.-C, Hazuka, C.D., Roth, R., Foletti, D.L., Heuser, J. and Scheller, R.H.
(1998) Subunit composition, protein interactions and structures of the mammalian
brain sec6/8 complex and septin filaments. Neuron 20:1 1 1 1-1 122.
193. Grindstaff, K.K., Yeaman, C, Anandasabapathy, N., Hsu, S.-C., Rodriguez-Boulan,
E., Scheller, R.H. and Nelson, WJ. (1998) Sec6/8 complex is recruited to cell-cell
contacts and specifies transport vesicle delivery to the basal-lateral membrane in
polarized epithelial cells. Cell 93:731-740.
194. Hay, J.C., Klumperman, J., Oorschot, V., Steegmaier, M., Kuo, C.S. and Scheller,
R.H. (1998) Localization, dynamics and protein interactions reveal distinct roles for
ER and Golgi SNAREs. J. Cell Biol. 141,7:1489-1502.
195. Namkung, Y., Smith, S.M., Lee, S.B., Skrypnyk, N.V., Kim, H.-L., Chin, H.,
Scheller, R.H., Tsien, R.W. and Shin, H.-S. (1998) Targeted disruption of the Ca 2+
channel P 3 subunit reduces N-type Ca 2+ channel activity and alters the voltage-
dependent activation of P/Q-type Ca 2+ channels in neurons. Proc. Natl. Acad. Sci.
USA 95:12010-12015.
1 96. Lillard, S.J., Chiu, D.T., Scheller, R.H., Zare R.N., Rodriguez-Cruz, S.E., Williams,
E.R., Orwar, O., Sandberg, M. and Lundqvist, J.A. (1998) Separation and
characterization of amines from individual atrial gland vesicles of Aplysia
californica. Analytical Chem. 70:3517-3524.
197. Brown, H., Larsson, O., Branstrom, R., Yang, S.-N., Leibiger, B., Leibiger, I., Fried,
G., Moede, T., Deeney, J.T., Brown, G., Jacobsson, G., Rhodes, C.J., Braun, J.E.A.,
Scheller, R.H., Corkey, B.E., Berggren, P.-O. and Meister, B. (1998) Cysteine string
protein (CSP) is an insulin secretory granule-associated protein regulating |3-cell
exocytosis. EMBO Journal 17:5048-5058.
198. Masuda, E.S., Huang, B.C., Fisher J.M., Ying, L. and Scheller, R.H. (1998)
Tomosyn binds t-SNARE proteins via a VAMP-like coiled coil. Neuron 21:479-
480.
1 99. Tahara, M., Coorssen, J.R., Timmers, K., Whalley, T., Scheller, R.H. and
Zimmerberg, J. (1998) Calcium disrupts the SNARE protein complex on sea urchin
egg secretory vesicles without blocking fusion. J. Biol. Chem. 273:33667-33673.
200. Weis, W. and Scheller, R.H. (1998) Snare the rod, coil the complex. Nature
395:328-329.
201. Prekeris, R., Klumperman, J., Chen, Y.A. and Scheller, R.H. (1998) Syntaxin 13
mediates cycling of plasma membrane proteins via tubulovesicular recycling
endosomes. J. Cell Biol. 143, 4:957-971.
202. Steegmaier, M., Yang, B., Yoo, J-S., Huang, B., Shen, M., Yu, S., Luo, Y. and
Scheller, R.H. (1998) Three novel proteins of the syntaxin/SNAP-25 family. J. Biol.
Chem. 273:34171-34179.
203. Hazuka, C.D., Foletti, D.L., Hsu, S.-C., Kee, Y., Hopf, F.W. and Scheller, R.H.
(1999) The sec6/8 complex is located at neurite outgrowth and axonal synapse-
assembly domains. J. Neurosci. 19:1324-1334.
80
204. Hazuka, C.D., Foletti, D.L. and Scheller, R.H. (1999) Nerve Terminal Membrane
Trafficking Proteins: from discovery to function. In: Neurotransmitter Release:
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U.K., pg. 81-125.
205. Yang, B., Gonzalez, L. G, Jr., Prekeris, R., Steegmaier, M., Advani, R.J. and Scheller,
R.H. (1999) SNARE interactions are not selective: Implications for membrane
fusion specificity. J. Biol. Chem. 274: 5649-5653.
206. Chao, D.S., Hay, J.C., Winnick, S., Prekeris, R., Klumperman, J. and Scheller, R.H.
(1999) SNARE membrane trafficking dynamics in vivo. J. Cell Biol. 144:869-881.
207. Hsu, S.-C, Hazuka, C.D., Foletti, D.L. and Scheller, R.H. (1999) Targeting vesicles
to specific sites on the plasma membrane: role of the sec6/8 complex. Trends In
Cell Biology 9: 150- 153.
208. Gonzalez, L. C., Jr. and Scheller, R.H. (1999) Regulation of membrane trafficking:
Structural insights from a Rab/effector complex. Cell 96:755-758.
209. Steegmaier, M., Klumperman, J., Foletti, D.L., Yoo, J.-S. and Scheller, R.H. (1999)
Vesicle-associated Membrane Protein 4 is implicated in rra/w-Golgi network vesicle
trafficking. Mol. Biol. of the Cell 10:1957-1972.
210. Chen, Y.A., Scales, S.J., Patel, S.M., Doung, Y.-C. and Scheller, R.H. (1999)
SNARE complex formation is triggered by Ca 2+ and drives membrane fusion. Cell
97:165-174.
211. Tsujimoto, S., Pelto-Huikko, M., Aitola,M., Meister, B., Vik-Mo, E.O., Davanger, S.,
Scheller, R.H. and Bean, A.J. (1999) The cellular and developmental expression of
hrs-2 in rat. European J. Neurosci. 11:3047-3063
212. Fung, E.T. and Scheller, R.H. (1999) Identification of a novel alternatively spliced
septin. FEES Letters 451:203-208.
213. Demo, S.D., Masuda, E., Rossi, A.B., Throndset, B.T., Gerard, A.L., Chan, E.H.,
Armstrong, R.J., Fox, B.P., Lorens, J.B., Payan, D.G., Scheller, R.H. and Fisher,
J.M. (1999) Quantitative measurement of mast cell degranulation using a novel
flow-cytometric annexin-V binding assay. Cytometry 36:340-348.
214. Chen, Y.A., Duvvuri, V., Schulman, H. and Scheller, R.H. (1999) Calmodulin and
Protein Kinase C increase Ca 2+ -stimulated secretion by modulating membrane-
attached exocytic machinery. J. Biol. Chem. 274:26469-26476.
215. Advani, R.J., Yang, B., Prekeris, R., Lee, K.C., Klumperman, J. and Scheller, R.H.
(1999) VAMP 7 mediates vesicular transport from endosomes to lysosomes. J. Cell
Biol. 146, 4:765-775.
216. Foletti, D.L., Prekeris, R. and Scheller, R.H. (1999) Generation and maintenance of
neuronal polarity: Mechanisms of transport and targeting. Neuron 23:641-644.
217. Bock, J.B. and Scheller, R.H. (1999) SNARE proteins mediate lipid bilayer fusion.
Proc. Natl. Acad. Sci. USA 96:12227-12229.
81
218. Prekeris, R., Foletti, D.L. and Scheller, R.H. (1999) Dynamics of tubulo-vesicular
recycling endosomes in hippocampal neurons. J. Neurosci. 19, 23:10324-10337.
219. Scales, S.J. and Scheller, R.H. (1999) Lipid membranes shape up. Nature 401:123-
124.
220. Prekeris, R., Yang, B., Oorschot, V., Klumperman, J. and Scheller, R.H. (1999)
Differential roles of syntaxin 7 and syntaxin 8 in endosomal trafficking. Mol. Biol.
of the Cell 10:3891-3908.
22 1 . Siidhof , T.C. and Scheller, R.H. (2000) Mechanism and Regulation of
Neurotransmitter Release. In: Synapses. [Cowan, W.M., Sudhof, T.C. and Stevens,
C., Eds.] Johns Hopkins University Press, pg. 177-216.
222. Jun, K., Piedras-Renteria, E.S., Smith, S.M., Wheeler, D.B., Lee, S.B., Lee, T.G.,
Chin, H., Adams, M.E., Scheller, R.H., Tsien, R.W. and Shin, H.-S. (1999) Ablation
of P/Q-type Ca 2+ channel currents, altered synaptic transmission, and progressive
ataxia in mice lacking the a, A -subunit. Proc. Natl. Acad. Sci. USA 96, 26:15245-
15250.
223 . Yang, B., Steegmaier, M., Gonzalez, L.C., Jr. and Scheller, R.H. (2000) nSecl binds
a closed conformation of syntaxinlA. J. Cell Biol. 148, 2:247-252.
224. Crowder, K.M., Gunther, J.M., Jones, R.A., Hale, B.D., Zhang, H.Z., Peterson,
M.R., Scheller, R.H., Chavkin, C. and Bajjalieh, S.M. (1999) Abnormal
neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc. Natl.
Acad. Sci. USA 96, 26:15268-15273.
225. Misura, K.M.S., Scheller, R.H. and Weis, W.I. (2000) Three-dimensional structure
of the neuronal-Secl -syntaxin la complex. Nature 404:355-362.
226. Masuda, E.S., Luo, Y., Young, C., Shen, M., Rossi, A.B., Huang, B.C.B., Yu, S.,
Bennett, M.K., Payan, D.G. and Scheller, R.H. (2000) Rab37 is a novel mast cell
specific GTPase localized to secretory granules. FEBS Letters 470:61-64.
227. Lin, R.C. and Scheller, R.H. (2000) Mechanisms of synaptic vesicle exocytosis.
Ann. Rev. Cell and Dev. Biol. 16:19-49.
228. Degtiar, V.E., Scheller, R.H. and Tsien, R.W. (2000) Syntaxin modulation of slow
inactivation of N-type calcium channels. J. Neurosci. 20:4355-4367.
229. Steegmaier, M., Lee, K.C., Prekeris, R. and Scheller, R.H. (2000) SNARE protein
trafficking in polarized MDCK cells. Traffic 2000 1:553-560.
230. Hatsuzawa, K., Hirose, H., Tani, K., Yamamoto, A., Scheller, R.H. and Tagaya, M.
(2000) Syntaxin 18, a SNAP receptor that functions in the ER, intermediate
compartment, and cw-Golgi vesicle trafficking. J. Biol. Chem. 275:13713-13720.
23 1 . Foletti, D.L., Lin, R., Finley, M.A.F. and Scheller, R.H. (2000) Phosphorylated
syntaxin 1 is localized to discrete domains along a subset of axons. J. Neurosci.
20:4535-4544.
82
232. Scales, S.J., Chen, Y.A., Yoo, B.Y., Patel, S.J., Doung, Y.-C. and Scheller, R.H.
(2000) SNAREs contribute to the specificity of membrane fusion. Neuron 26:457-
464.
233. Steegmaier, M., Oorschot, V., Klumperman, J. and Scheller, R.H. (2000) Syntaxin
17 is abundant in steroidogenic cells and implicated in smooth endoplasmic
reticulum membrane dynamics. Mol. Biol. of the Cell. 11:2719-2731.
234. Prekeris, R., Klumperman, J. and Scheller, R.H. (2000) Syntaxin 1 1 is an atypical
SNARE abundant in the immune system. European J. Cell Biol. 79: 771-780.
235. Bezprozvanny, I., Zhong, P., Scheller, R.H. and Tsien, R.W. (2000) Molecular
determinants of the functional interaction between syntaxin and N-type Ca 2+ channel
gating. Proc. Natl. Acad. Sci. USA. 97, 13943-13948.
236. Scales, S.J., Bock, J.B. and Scheller, R.H. (2000) The specifics of membrane
fusion. Nature 407:144-146.
237. Prekeris, R., Klumperman, J. and Scheller, R.H. (2000) A Rabl 1/Ripl 1 protein
complex regulates apical membrane trafficking via recycling endosomes. Molecular
Cell.6, 1437-1448.
238. Nave, K.-A. and Scheller, R.H. (2000) Neuronal and glial cell biology. Editorial
Overview. Curr. Opin. Neurobiology 10, 541-542
239. Chen, Y.A. and Scheller, R.H. (2001) SNARE-mediated membrane fusion. Nature
Reviews!, 98-105
240. Hua, Y. and Scheller, R.H. (2001) Three SNARE complexes cooperate to mediate
membrane fusion. Proc. Natl. Acad. Sci. USA, 98, 8065-8070.
241 . Foletti, D.L., Blitzer, J.T.and Scheller, R.H. (2001) Physiological modulation of
rabphilin phosphorylation. J. Neuroscience 21, 5473-5483.
242. Foletti, D.L. and Scheller, R.H. Developmental regulation and specific brain
distribution of phosphorabphilin. J. Neuroscience 21, 5461-5472.
243. Chen, Y.A., Scales, S.J., Scheller, R.H. (2001) Sequential SNARE assembly
underlies priming and triggering of exocytosis. Neuron 30, 161-170.
244. Matern, H.T., Yeaman, C., Nelson, WJ. and Scheller, R.H. (2001) The Sec6/8
complex in mammalian cells: characterization of mammalian Sec3, subunit
interactions, and expression of subunits in polarized cells. Proc. Natl. Acad. Sci.,
USA, 98, 9648-9653.
245. Chen, Y.A., Scales, S.J., Duvvuri, V., Murthy, M., Patel, S.M., Schulman, H. and
Scheller, R.H. (2001) Calcium regulation of exocytosis in PC12 cells. J. Biol.
Chem. 276, 26680-26687.
246. Prekeris, R., Davies, J.M. and Scheller, R.H. (2001) Identification of a novel
Rabl 1/25 binding domain present in eferin and Rip proteins. J. Biol. Chem. 276,
38966-38970.
83
247. Chen, Y.A., Scales, S.J., Jagath, J.R.; Scheller, R.H. (2001) A discontinuous SNAP-
25 C-terminal coil supports exocytosis. J. Biol. Chem. 276, 28503-28508.
248. Misura, K.M.S., Gonzalez, L.C., Jr., May, A.P., Scheller, R.H., Weis, W.I. (2001)
Crystal structure and biophysical properties of a complex between the N-terminal
SNARE region of SNAP25 and syntaxin la. 7. Biol. Chem. 276, 41301-41309.
249. Bock, J.B., Matern, H.T, Peden, A.A and Scheller, R.H. (2001) A genomic
perspective on membrane compartment organization. Nature 409, 839-841.
250. Gonzalez, L.C., Jr., Weis, W.I. and Scheller, R.H. (2001) A novel SNARE N-
terminal domain revealed by the crystal structure of Sec22b. J. Biol. Chem. 276,
24203-24211.
25 1 . Peden, A. A., Park, G. Y. and Scheller, R.H. (200 1 ) The di-leucine motif of vesicle-
associated membrane protein 4 is required for its localization and AP-1 binding. J.
Biol. Chem276, 49183-49187
252. Finley, M.F.A., Patel, S.M., Madison, D.V., ScheUer, R.H. (2002) The core
membrane fusion complex governs the probability of synaptic vesicle fusion but not
transmitter release kinetics. J. Neuroscience, 22, 1266-1272.
253. Scales, S.J., Yoo, B.Y., and Scheller, R.H. (2001) The ionic layer is required for
efficient dissociation of the SNARE complex by a-SNAP and NSF. Proc. Natl.
Acad. Sci, USA, 98, 14262-14267.
254. Scales, S.J., Finley, M.F.A., and Scheller, R.H. (2001) Fusion without SNAREs?
Science 294,1015-1016.
255. Martinez-Menarguez, J.A., Prekeris, R., Oorschot, V.M.J., Scheller, R.H., Slot, J.W.,
Geuze, H.J., Klumperman, J. (2001) The peri-Golgi vesicles contain retrograde but
not anterograde proteins consistent with the cisternal progression model of intra-
Golgi transport. J. Cell Biol. 155, 1213-1224.
256. Misura, K.M.S., Bock, J.B., Gonzalez, L.C., Jr., Scheller, R.H., Weis, W.I. (2002)
Three dimensional structure of the amino terminal domain of syntaxin 6, a SNAP-
25 C homologue. Proc. Natl. Acad. Sci. USA, 99, 9184-9189.
257. Scales, S.J., Hesser, B.A.; Masuda, E. S. and Scheller, R.H. (2002) Amisyn, a novel
syntaxin-binding protein that may regulate SNARE complex assembly. J. Biol.
Chem. 277,28271-28279.
Submitted
Prekeris, R., Davies, J.M., Matern, H.T., ScheUer, R.H. ( ) Ripl 1 and nRipl 1 are Rabl 1/25
interacting proteins.
Smith, S.M., Bergsman, J.B., Scheller, R.H., Tsien, R.W. ( ) Decreases in extracellular Ca
!+ modulate membrane currents at single rat cortical nerve terminals.
Murthy, M., Garza, D., ScheUer, R.H., Schwarz, T.L. (2003) Mutations in the exocyst
component Sec5 disrupt neuronal membrane traffic, but neurotransmitter release
persists
84
85
INDEX-Richard Scheller
actin gene research, 1 8
Aplysia neuroscience research, 19, 22-23,
26-27
Axel, Richard, 2 1-22 ,38
Berg, Paul, 10
Bolivar, Paco, 56
Botstein, David, 38
Boyer, Herb, 7, 8, 10, 49, 50
California Institute of Technology, 4-18,
48-54
Campbell, Alan, 25
City of Hope Medical Center/litigation, 6,
48,51-52,53,54
Cohen-Boyer recombinant DNA patent, 42,
54
Cohen, Stanley N., 10
Columbia University, 18-23
commercialization of biology, 55-57
consulting work, Scheller s, 29
Crick, Francis, 22
Davidson, Eric, 13, 17, 18, 21
Davidson, Norman, 13
Dickerson, RicharoVDickerson lab, 4, .6-7,
10-11,48,56
DNA cloning, 8, 9, 49-50
DNA libraries, 13, 22
DNA linkers/linking, 8, 9-10, 12, 24, 49
gene expression, 12
Genentech
corporate culture, 35-36, 57
corporate goals, 33-35
executive committee, 39, 40, 59
growth hormone project, 54
insulin project, 51, 54
pharmaceutical development, 45
Research Review Committee, 46
Scheller s postdoctoral fellows,
43-44
Scheller s programmatic changes,
42-43
somatostatin project, 48-54
stock options, 54-55, 56
Gilbert, Walter, 9, 48-49, 56
Goeddel, Dave, 36, 38
Goodman, Corey, 25
Hall, Stephen, 48
Henner, Dennis, 37, 38, 39
Heyneker, Herb, 7, 8, 56
Hoffmann-La Roche, 46
Hood, Leroy, 13, 16
Howard Hughes Medical Institute, 27, 29-30
Lasky, Larry, 59
Lavigne, Lou, 59
intellectual property protection, 40-42
Itakura, Keiichi, 5, 6-8, 1 1, 49, 50, 51, 54,
56
Jacob, Francois, 4
Kandel, Eric, 19, 22-23
Khorana, Gobind/Khorana method, 5-6, 8,
49,50
Kiley, Thomas, 53
lac operator cloning research, 7-8
lac operon research, 6, 8, 11, 12, 49
lac represser protein research, 4-5, 7
Levinson, Arthur, 33-34, 37, 38, 39
Maniatis, Tom, 13
Martin, Dave, 39
McConnell, Susan, 27
Monod, Jacques, 4
Narang, Saran A., 50
neurobiology/neurobiology research, 19-21,
22-23, 25-27, 37-38
NTH guidelines, 14-15, 50
patents/patenting, 40-42, 54
Pauling, Linus, 7
Perutz, Max, 6
Ptashne, Mark, 9
86
recombinant DNA biohazard controversy,
13-16,50
recombinant DNA technology, 10, 12-13,
1 8, 23 and passim
reductionism in science, 18-19
restriction enzymes, 8, 16, 49
Riggs, Art, 5,6,11,50,54
Riggs-Itakura patent, 54
science/scientists in industry and academia,
29, 37, 44
scientific publication, 3 1-32
Seeburg, Peter, 9
Sinsheimer, Robert, 13, 15-16
Stanford University
Beckman Center, 27
Department of Biological Sciences,
24-27
Department of Molecular & Cellular
Physiology, 27-28
patenting at, 41, 42
Scheller as Hughes Fellow at, 27-30
Swanson, Bob, 36, 50, 51, 53
synthetic DNA, 5-11, 48-54
Terman, Frederick E., 57
Ullrich, Axel, 9
University of Wisconsin, 3
biochemistry department, 2
Enzyme Institute, 2
x-ray crystallography, 3, 4, 6, 10
Yanofsky, Charles, 25, 28
Sally Smith Hughes
Graduated from the University of California, Berkeley, in 1963 with an A.B.
degree in zoology, and from the University of California, San Francisco, in 1966
with an M.A. degree in anatomy. She received a Ph.D. degree in the history of
science and medicine from the Royal Postgraduate Medical School, University
of London, in 1972.
Postgraduate research histologist, the Cardiovascular Research Institute,
University of California, San Francisco, 1966-1969; science historian for the
History of Science and Technology Program, The Bancroft Library, 1978-1980.
Presently research historian and principal editor on medical and scientific topics
for the Regional Oral History Office, University of California, Berkeley. Author
of The Virus: A History of the Concept, Sally Smith Hughes is currently
interviewing and writing in the fields of AIDS and molecular
biology/biotechnology.
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